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Specialty grand challenge article, the immunology of parasite infections: grand challenges.

• School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia

Introduction

Parasitic diseases continue to be a major cause of morbidity and mortality worldwide, with billions of people at risk of infection, often with multiple parasites ( https://www.who.int ). Despite this global impact, there are limited treatment options for most infections and only one human vaccine, which is moderately effective against malaria ( Stutzer et al., 2018 ; Zavala, 2022 ). The key to controlling parasite infection is to better understand the host immune response to these pathogens and to determine how this can be exploited to protect the host from infection and/or the pathological consequences of infection. However, this is a formidable task. By virtue of a dependency on a host for cyclical transmission and millennia of co-evolution with their hosts, parasites have developed multifaceted, often life-cycle stage-specific strategies to utilize, evade, modulate, and/or regulate the host immune response to avoid elimination and ensure their long-term survival to mature and complete their life cycle ( Yazdanbakhsh and Sacks, 2010 ).

Through decades of research many of these mechanisms have been characterized ( Chulanetra and Chaicumpa, 2021 ), and can be subdivided into different tactical approaches including, an ability to become camouflaged by host factors, inhabiting immune privileged sites, expressing stage specific antigens, secreting components that mimic host factors, driving the differentiation of immune cell phenotypes, and regulating the responsiveness of host immune cells. Importantly, these studies have provided critical insights into fundamental mechanisms of human immunology. Most notably, murine experimental leishmaniasis was the first model to confirm the biological significance of the Th1/Th2 paradigm in vivo ( Scott, 1989 ). While these discoveries have significantly contributed to our current knowledge of the interaction between parasites and their host’s immune response, there is still an incomplete understanding of this relationship. Future research will be informed by concomitant developments in immunological, molecular and cell culturing techniques and innovations, such as immune-metabolomics, cell signaling systems, imaging mass spectrometry, organoid culture, microfluidics, vaccine technology (and others). However, there are also important considerations that are specific to parasite infection, and I believe represent some of the grand challenges facing this field of parasitology.

Grand challenge 1: Are parasite infections a necessary evil – is there a future for parasite derived therapeutics?

While parasites have clearly benefited from the development of immune-modulatory mechanisms, this evolutionary adaptation to support their long-term survival may have unwittingly positioned them as a necessary component of the human immune response ( Fumagalli et al., 2009 ; Jackson et al., 2009 ). Due to their ubiquitous nature in human populations, it has been proposed that their presence provided the regulatory networks to keep activation of immune responses in check and drive the homeostatic resolution of inflammation. As a result of this co-dependence, the removal of parasites from human populations through increased sanitation and urbanization establishes an imbalance in the immune system, thereby increasing susceptibility to the inappropriate activation of inflammatory responses, resulting in immune-mediated disease ( Jackson et al., 2009 ; Rook, 2010 ; Allen and Maizels, 2011 ). Indeed, there is compelling epidemiological evidence of an inverse correlation between the prevalence of endemic helminth infections and the incidence of immune-mediated disease in human populations worldwide. Furthermore, there is now a substantial body of experimental evidence in animal models showing that live parasite infection, or the administration of parasite-derived proteins/peptides, can prevent progression of inflammatory disease ( Maizels, 2020 ; Ryan et al., 2020 ). Understandably, much of this research has been performed from the perspective of parasitology research, rather than a translational, clinical pathway. However, this means that the most appropriate pre-clinical models of immune-mediated disease have not always been utilized and that fundamental knowledge of the pharmacokinetics, mechanisms of action, and toxicity of the parasite molecules is often lacking ( Sobotková et al., 2019 ).

The challenge here will be the establishment of a concerted, collaborative effort between research and industry partnerships. This will more effectively inform research activity to better position parasite-derived therapeutics as a consideration for clinical applications by the pharmaceutical industry and drive this solid (and encouraging) evidence of efficacy from bench to bedside.

Grand challenge 2: Parasites do not live alone – a holistic approach is needed

In the same way the modulation of immune responses by parasites may impact the course of immune-mediated diseases, parasites can also significantly alter the developing immune response to concurrent infections, which consequently impacts the progression and severity of illness, and vice versa ( Hassan and Blanchard, 2022 ). This is a particular concern for endemic human populations (and most animals), in which parasite infections occur against a background of co-infection with other parasites and other microbial pathogens ( Venter et al., 2022 ). However, there is no clear consensus as to which concurrent infections are protective or which increase the severity of disease, nor is there a clear understanding on how the presence of multiple pathogens specifically influences the host immune response ( Mabbott, 2018 ). Despite the important consequences of co-infection, the potential interactions among parasites are rarely considered in either clinical settings or in immunological analysis of models of infection. However, understanding how the host immune response behaves in this setting is critical to informing possible strategies for treatment and/or infection control.

In addition to the presence of pathogenic organisms, trillions of commensal microorganisms, inhabit the mammalian body. This microbiota underpins the health of its host with hypothesized impacts on inflammation, immune development, and disease outcomes. Evidence is emerging that the host microbiome plays a contributory role in the parasite’s modulation of host immune responses. Multiple studies have now shown that the presence of parasites in the intestine changes the overall composition of bacterial species in the gut ( Zaiss and Harris, 2016 ; Chabé et al., 2017 ), which in turn influences inflammation and health ( Ramanan et al., 2016 ; Coakley and Harris, 2019 ). Whether the host immune response to the parasite infection is altering the resident microbiota, and/or whether the parasites and their secreted products are directly modifying the composition of the microbiome remains to be elucidated.

In addition to the host microbiota, parasite-associated microbiota also shapes the host immune response and the pathological outcome to disease ( Ives et al., 2011 ; Yurchenko and Lukeš, 2018 ). However, despite the identification of the Wolbachia endosymbiont of filarial nematodes more than 20 years ago ( Williams et al., 2000 ), only a handful of parasite species have had their associated microbiome characterized ( Dheilly et al., 2019 ). As a result, there is limited insight into the functional relationship between the parasite, its microbiome and the host and the consequences that this has upon the immune response and the outcome to infection.

This evidence of the involvement of microorganisms in the parasite-host relationship is a reminder of the complexity of a mammalian biological community. Disentangling the interactions between parasites and hosts, their respective microbiota, and microbial pathogens in the parasite’s direct environment, and understanding how these influence the host immune response will be a challenge. A holistic approach is required, accounting for all contributors, to elucidate the critical determinants of risk and benefit to host health.

Grand challenge 3: The importance of the host – is the lab mouse an adequate model?

The majority of research elucidating the fundamental mechanisms of parasite immune modulation/evasion, has been performed in experimental animals, particularly rodents. This methodology has been driven by the broad availability of different strains (and transgenics) of mice and a multitude of murine specific reagents to support the characterization of immunological networks and cellular phenotypes. Although this approach has been central to the identification and characterization of immune responses during infection, it has likely only illuminated a small fraction of the heterogeneity in host-parasite immune relationships.

While laboratory mice have served well as models of mammalian immune function, generating many successful translational therapies to the clinic, it has been now well established that the immune cell populations in these mice are not equivalent to adult mammals and thus do not always exhibit corresponding immune responses to infection ( Abolins et al., 2017 ; Masopust et al., 2017 ). The phenotype and functional activity of an animal’s immune response to infections is informed by their environment. In the laboratory setting, mice are generally housed and maintained in filtered, microbial free, controlled environments which is a contributing factor to the immunological divergence between lab mice and wild mice (and other mammals) ( Graham, 2021 ), a difference which has been shown to influence the outcome of parasite infection. While the lab strain of C57BL/6 mice are resistant to high infectious doses of the intestinal nematode, Trichuris muris , when these mice were exposed to outdoor environments, they displayed a reduced capacity to produce Th2 type immune responses and as a result their susceptibility to infection was significantly increased ( Leung et al., 2018 ). The factors that contributed to this change in immune response were not determined, but it is a scenario that should be extended to the study of other parasite infections.

Despite the vast number of identified helminths and protozoan parasites ( Cox, 2002 ), our assumptions regarding the immune response to parasite infection has largely been formed from studies of only a handful of parasites that have the capacity to infect a laboratory mouse. Furthermore, the primary mechanisms of immune modulation attributed to helminths has generally been elucidated through infections with nematodes that have only adapted to infect a rodent host ( Heligmosomoides polygyrus , Trichuris muris). While these may have been proven to be an adequate model for human intestinal helminth infection, there is no equivalent murine model for many of the larger tissue dwelling helminth parasites from which to elucidate immune modulatory mechanisms throughout their life cycle, as the tissue damage that ensues during maturation and migration of the adult parasites in these cases is often too severe for a murine host. For these parasites, large animal hosts are required to fully understand the host-parasite immune relationship, but the logistics, ethics, cost, and lack of suitable analytical reagents is often prohibitive.

To establish an infection in these models (mouse and large animal), in general, a single large infectious dose is administered to the host and the immune response and corresponding pathogenesis is tracked over time. Once again, although this is a necessary approach to gain some insight into the developing immune response to the presence (and development) of a pathogen, it is unlikely to represent a naturally occurring infectious dose. As such, it is important to consider how the pathology resulting from a high parasite burden is impacting the developing immune response and determine whether this is producing an artificial representation of the true parasite-host relationship. In addition, this experimental protocol of infection may be negatively impacting the evaluation of vaccine candidates. The potent immune modulation induced by such high infectious doses of parasites likely suppresses the antigen-specific responses induced by vaccination. In contrast, a low dose (or trickle dose in field trials for animal hosts) would better represent the real-world challenge for a vaccine.

Combined, these observations highlight the challenge in selecting models of parasite infection that authentically reflect that of their natural hosts and therefore accommodate the characterization of the true phenotype and functional activity of the host immune response during all stage of infection.

Grand challenge 4: Expanding the characterization of parasite-host communication

A critical aspect to uncovering the mechanisms by which parasites control their host’s immune response is to characterize the communication signals used by the parasite. Accordingly, over several decades the excretory/secretory (ES) products of many parasites have been characterized. Starting with the identification of the proteins released by the parasites, the development of modern techniques enabled more in-depth characterization and expanded the repertoire of secreted molecules to glycans, lipids, miRNAs, small molecules and metabolites ( Maizels et al., 2018 ; Ryan et al., 2022 ). Many of these components are homologous to host molecules involved in the regulation of immunity, thus endowing them with the capacity to mimic host signaling networks to modulate the immune response ( Smyth et al., 2018 , Ricafrente et al., 2021 ). Furthermore, some of these parasite derived molecules are secreted by the parasite within extracellular vesicles (EV), which are taken up by host cells ( Wu et al., 2019 ), thus creating a cross-species channel of communication and facilitating the parasites with access to the intracellular machinery of host immune cells. A greater understanding of the biogenesis of parasite EVs and the selection and sorting of their cargo will transform our understanding of the parasite-host relationship, build on the existing knowledge of mechanisms of parasite immune modulation, and provide new targets for anti-helminthic strategies.

Grand challenge 5: The characterization of a protective immune response - development of an effective vaccine

Ultimately, the study of parasite immunology is driven by the ambition of identifying effector mechanisms to eliminate the parasite and prevent future infections. However, despite the extensive characterization of the parasite’s mechanisms of immune modulation and immune evasion, the ability and capacity to therapeutically intervene in these infections remains rudimentary. Fundamentally, development of an effective parasite vaccine remains hampered by a lack of understanding of what constitutes a protective immune response. Although multiple clinical trials have suggested efficacy of putative vaccine candidates, most have not translated to the field.

Perhaps it is time to challenge thinking and the approach to parasite vaccine development. One question that needs to be asked is how good a vaccine against any specific parasite needs to be? After all, the only human parasite vaccine on the market is estimated to provide just a short-lived protection of ~34% ( Zavala, 2022 ), an efficacy that would not be accepted by any standard vaccine development program. However, by reducing severe disease in young children, and when administered in conjunction with other control measures it may decrease exposure to the parasite, and therefore the vaccine will contribute to minimize or eliminate the clinical consequences of infection. So rather than trying to achieve resistance, perhaps the goal should be reimagined with the aim of minimizing or eliminating the pathological consequences of infection.

Invitation to the immunology and immune evasion section of frontiers in parasitology

These grand challenges are not an exhaustive list, and as such The Frontiers in Parasitology Immunology and Immune Evasion Section is calling on the research community to initiate further conversation, to inspire and to provide informed guidance regarding the advances and research questions that are most important to them. Accordingly, we have released a call for reviews covering any topic in Parasite Immunology and Immune Evasion and currently have two open Research Topics named “Insights into Recent Advances and Future Perspectives in Parasite Immunology” and “Helminth Infection and Regulation of Unrelated Diseases”. We look forward publishing experimental work, clinical trials, perspectives, opinions, and reviews in this field of research.

Author contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: parasite, immunology, immune-modulation, microbiota, helminth-therapy, vaccine

Citation: Donnelly S (2022) The immunology of parasite infections: Grand challenges. Front. Parasitol. 1:1069205. doi: 10.3389/fpara.2022.1069205

Received: 13 October 2022; Accepted: 25 October 2022; Published: 08 November 2022.

Edited and Reviewed by:

Copyright © 2022 Donnelly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sheila Donnelly, [email protected]

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• Published: 15 June 2019

Investigating immune responses to parasites using transgenesis

• Mebrahtu G. Tedla   ORCID: orcid.org/0000-0002-0903-3269 1 ,
• Alison L. Every 1   nAff2 &
• Jean-Pierre Y. Scheerlinck 1  

Parasites & Vectors volume  12 , Article number:  303 ( 2019 ) Cite this article

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Parasites comprise diverse and complex organisms, which substantially impact human and animal health. Most parasites have complex life-cycles, and by virtue of co-evolution have developed multifaceted, often life-cycle stage-specific relationships with the immune system of their hosts. The complexity in the biology of many parasites often limits our knowledge of parasite-specific immune responses, to in vitro studies only. The relatively recent development of methods to stably manipulate the genetic make-up of many parasites has allowed a better understanding of host-parasite interactions, particularly in vivo . In this regard, the use of transgenic parasites can facilitate the study of immunomodulatory mechanisms under in vivo conditions. Therefore, in this review, we specifically highlighted the current developments in the use of transgenic parasites to unravel the host’s immune response to different life-cycle stages of some key parasite species such as Leishmania , Schistosoma , Toxoplasma , Plasmodium and Trypanosome and to some degree, the use of transgenic nematode parasites is also briefly discussed.

Today, despite available treatments, more than 2 billion people are suffering from chronic infections with parasites, resulting in considerable morbidity [ 1 ]. Chronic infections develop because these parasites escape destruction by the immune system, arguably helped by their complex biology [ 2 ]. Parasitic infections and the host’s immune responses are the result of dynamic co-evolution of the host and the parasite’s complex life-cycle with each life stage resulting in a different interaction with the immune system [ 3 , 4 ]. Despite significant progress studying the biology of these parasites, there is still incomplete understanding of the interaction between the host’s immune response and these parasites [ 5 ].

Recent progress has been made in the development of transgenic parasites allowing for the structural and functional analysis of specific gene products [ 6 ], by for example, knocking-in or knocking-out target genes followed by functional analysis, in vivo [ 7 ]. For genetic manipulation of protozoan parasites ( Toxoplasma , Plasmodium and Leishmania ), robust systems were developed based on classical molecular biology methods such as microinjection, chemical transfection and electroporation, resulting in early advances in the understanding of the interactions between the immune system and these parasites. In contrast, for multicellular parasites these methods were not optimal and therefore, these parasites are now manipulated using transduction based on retroviral vectors.

Another breakthrough was the discovery that parasites possess the RNA-dependent gene silencing machinery and hence RNA interference (RNAi) has been applied to specifically downregulate genes, as opposed to producing a completely knocking-out of the gene of interest. For multicellular organisms such as Schistosoma mansoni lentivirus transduction was necessary to allow a highly efficient introduction of the foreign DNA [ 8 ]. Despite such progress, there are still limitations in gene manipulation approaches in multicellular parasites due to their diverse cellular elements and tissues, and complex life-cycles [ 9 ].

This review highlights the contributions made by studies on transgenic parasites to the understanding of host-parasite interactions and other applications of genetic manipulations in parasites were specifically omitted.

The databases PubMed and Web of Science were searched using keywords, including “transgenesis”, “parasite” and “immune response”. The search was conducted during the period of 2017 and 2018 and all the relevant scientific publications were screened following the procedure illustrated in the diagram below (Fig.  1 ). To meet the inclusion and exclusion criteria, only papers containing information on transgenic parasites and immune response study were included during the screen and non-published data or theses were not included for this study purpose.

A flow diagram for the identification and screening of research articles for the current review

Expression of model antigens in parasites

One way of demonstrating protective cell-mediated immune responses is with the help of parasites transfected with putative protective antigens, followed by cell-transfer experiments to confirm the protective immune response. One special case of this approach consists of using antigens for which T cell receptor (TCR) transgenic mice have been generated [ 10 ]. These mice express the TCR specific for a peptide present in the model antigen presented in association with either MHC class II or I. For example, OT-II mouse—on a C57Bl/6 mouse background—express a TCR, which specifically recognises a peptide from chicken ovalbumin (OVA, amino acids 323–339) in association with MHC class II. In contrast, OT-I mouse express a transgene encoding a TCR specific for a short peptide fragment of OVA (amino acids 257–264) presented by MHC class I [ 11 ]. These mice can be used experimentally as a source of naïve T cells with a known specificity [ 12 ] and, hence, offer interesting tools to study T cell responses to these parasites. For example, transgenic Plasmodium berghei parasites were generated to express MHC class I- and II-restricted T cell peptide epitopes [ 13 ], recognised by TCR transgenic (HNT, DO11.10, and B6) mice, which were then used to elucidate the role of T cells in protective immunity to blood stage parasites. To achieve this, a T cell polytope was generated by artificially linking several T cell epitopes together including (i) MHC-I and II restricted epitopes from OVA, (ii) MHC-I restricted epitope from glycoprotein B of HSV-1, and (iii) MHC-I and II restricted epitopes from influenza virus strain PR8 hemagglutinin [ 13 ]. Blood stage of parasites transduced with this polytope were able to induce not only antigen-specific CD4 + T cells but, more unexpectedly, also antigen-specific CD8 + T cell responses via cross-presentation by CD8α + subsets of dendritic cells (DCs). While these antigen-specific CD8 + T cells did not contribute to protection against the blood stage of Plasmodium infection, they played a key role in the initiation of cerebral malaria (CM) and hence are important in the pathology of this infection [ 13 ]. This unexpected finding would have been very difficult to discover without the use of transgenic parasites, hereby demonstrating the usefulness of this technique for the analysis of immune responses to parasites.

Model antigens (i.e. antigens that are not naturally occurring in any pathogen), such as OVA, are frequently expressed in pathogens to investigate the major determinants and pathways influencing T cell responses. In contrast to pathogen-antigens, model antigens have never been subjected to evolutionary pressure and as a result they are unlikely to have been selected to induce biased immune responses. Thus, studying the immune response to these antigens not only allows for the use of many available reagents, but also facilitates the isolation of effects due to the antigen from these due to the pathogen. However, these model antigens are also artificial and therefore may not necessarily reflect the immune responses against pathogen antigens. Nevertheless, they represent useful tools in furthering our understanding of immune responses associated with parasites.

Other examples of the use of model antigens are studies showing that OT-II CD4 + and OT-I CD8 + T cells specifically recognize epitopes of OVA in Toxoplasma gondii including strains expressing OVA such as type I strain (expressing RH-OVA) and type II strains (expressing Pru-OVA). By injecting these transgenic parasites into mice, Pru-OVA can activate the DCs to produce cytokines within the draining lymph node and a large population of endogenous OVA-specific CD8 + T cells can be generated. Mice infected with RH-OVA have fewer DCs and OVA-specific CD8 + T cells [ 14 ]. The expression of model antigens in parasites allows not only the study of the major parasite determinants influencing immune responses, but also the exploration of the effects of the antigens’ subcellular localization on the induction of T cell response.

The expression of model antigens in different part of the parasite using transgenesis have been frequently used to determine the effect of antigen localisation on the host’s immune recognition. For example, P. berghei have been developed expressing recombinant proteins either in the cytosol or the parasitophorous vacuole membrane (PVM) to assess whether the sub-cellular location can influence T cell responses. OVA and mCherry conjugated with P. berghei heat-shock proteins such as HSP-70 were expressed in the cytoplasm. However, OVA gene sequence conjugated with the HEP17 (EXP1) promoter showed a low level of expression in the PVM [ 15 ]. Although both transgenic P. berghei lines induce OVA-specific CD8 + and CD4 + T cell responses, PVM-expressed OVA-HEP17 (EXP1) induced higher proliferation of OT-II and OT-I T cells than cytoplasma-expressed OVA-mCherry-HSP70, suggesting that antigen localisation within the parasite affects T cell recognition. Unconjugated OVA is not expressed in the cytoplasm of the parasite and more importantly here, the location and the degree of expression in the parasite also influence T cell responses [ 15 ]. The recognition of transgenic cytoplasmic OVA in Plasmodium by CD8 + T cells during different life-cycle stages of infection was also described [ 16 ]. However, those parasites were unable to induce a CD4 + T cell response in vivo [ 17 ]. A possible explanation for this dichotomy is that the localisation of the antigen in parasites drives the antigen processing pathways used in antigen presenting cells [ 18 ]. Furthermore, OVA expressed by blood stage P. berghei showed cross-presentation of the antigen by CD8α + antigen presenting cells in association with MHC class I and II inducing both CD8 + and CD4 + T cells [ 15 ].

Plasmodium spp. are not the only parasites for which the location of the antigen affects recognition by T cells. Indeed, Toxoplasma gondii has been engineered to express recombinant OVA either in the cytosol or to be secreted into the parasitophorous vacuole [ 19 ]. These studies demonstrated that only the secreted form of OVA, can stimulate CD4 + T cells and induce IFN-γ production (Fig.  2 ). Similarly, LacZ-expressing parasites containing CD8 T cell epitopes could only stimulate CD8 + T cell when the LacZ protein was expressed in a PV-secreted form but not when expressed as a cytosolic form [ 20 ]. In addition, T. gondii expressing secreted OVA in the PV, but not those that express a cytosolic OVA, were able to stimulate OVA-specific CD4 + T cells [ 21 ]. Therefore, antigens secreted in the PV are more effective at activating both CD4 and CD8 T cell. PV-secreted antigens might be more efficiently released from infected cells and hence more antigen could be available to be processed through the MHC II pathway. Similarly, PV-secreted antigens are transported more effectively from the PV into the host cell cytoplasm possibly through cross-presentation dependent of the TAP transporter.

The site of OVA expression inside the transgenic parasite has influenced the cellular immune responses in which cytosolic OVA leads to stimulation of CD4 + T cells and IFN-γ production. To confirm whether OVA expressing transgenic T. gondii can induce T cell proliferation, CD4 + T cells were labelled with CFSE and the in vitro response of the cells showed the cytosolic OVA failed to show any T cell response, but OVA expressed at the parasitophorous vacuole induced T cell proliferation [ 25 ]

Furthermore, Leishmania spp. have also been used to study the effect of expressed antigens at different locations on the induction of T cell responses. For example, OVA has been used as a reporter gene by integrating it into the genomic DNA of Leishmania donovani , allowing the isolation of OVA-expressing amastigotes. Mice adoptively transferred with OVA-specific OT-I T cells and infected with OVA-transgenic parasite demonstrated that OVA could be recognised in the context of MHC class I and in the same study a reduction in hepatic and splenic parasite burden was observed [ 22 ]. Furthermore, in a follow-up experiment, OVA expressed on the plasma membrane led to a significant activation of CD4 + T cells [ 23 ]. The ability of a fusion protein containing OVA (NT-OVA), expressed by transgenic parasites in either a secreted form or an intracellular form, to stimulate OT-I CD8 + T cells was investigated [ 24 ]. Dendritic cells infected by Leishmania major transfected with secreted NT-OVA could activate naïve OT-I cells while non-secreted (i.e. intracellular) NT-OVA was unable to achieve this outcome, possibly because less OVA was available in the phagosomes [ 24 ]. Indeed, high concentrations of NT-OVA might be required in the phagosomes, to allow for the relatively inefficient cross-presentation of OVA present in the phagosome (where the parasite resides), through the MHC I pathway. DCs pulsed with heat-killed parasites were also unable to activate naïve OT-I cells, possibly because not enough antigen can accumulate in the phagosomes and hence transit via cross-presentation to MHC I. Interestingly, infected macrophages, which generally lack the antigen cross-presentation pathway, were unable to activate naïve OT-I cells when infected with L. major transfected with either the secreted or the intracellular form of NT-OVA (Fig.  3 ), corroborating the results suggesting the use of cross-presentation in this process. Macrophages were able to activate primed OT-I cells but 20 times less efficiently, compared to DCs. Taken together, these results suggest that L. major antigens secreted in the phagosomes of DCs, but not macrophages, can cross-present antigenic peptides to MHC I leading to CD8 + T cells activation, while the local accumulation of intracellular antigens is insufficient to allow cross-presentation and hence no CD8 activation can occur. Interestingly, as noted above, similar conclusions were made for T. gondii except that in contrast to the Leishmania , T. gondii antigens in the PV do not seem to go directly into the MHC II antigen processing pathway.

The expression of two OVA epitopes (NT-OVA and SP-OVA) in L. major parasite showed different type of T cell responses when exposed to dendritic cells and macrophages in vitro separately. Whereas, injection of both OVA epitope transgenic parasites into mice after adoptive transfer of OVA specific OT-I T cells showed only an induction of CD8 + T cells in vivo

Expression of reporter genes for parasite tracking and immune cell characterization

The advent of model reporter gene technology has facilitated the understanding of many cellular responses to parasites with distinct phenotypic properties from the system being investigated.

Due to various limitations of light microscopy-based in vivo imaging techniques, the direct investigation of different events in the host has been impossible until recently [ 25 ]. One of the earliest studies of immune responses in vivo involved adoptive transfer of T cells, B cells, and DCs to a recipient host [ 26 ]. In the same context, different fluorescent dyes such as CFSE have been used for the labelling and short-term tracking of the cells as they migrate in the host. However, as cell division or activation results in dilution of the dye, tracking of the cell population over longer time periods was not possible in this model [ 25 ]. To overcome such difficulties, different fluorescent proteins have been expressed under promoters specific for various cell types such as, CD4 + T cells, CD8 + T cells, macrophages, DCs, and neutrophils and this has allowed long-term investigation of cell trafficking during in vivo immune responses [ 25 ]. This approach has been combined with the expression of different reporter genes in the parasite [ 27 ]. For example, transgenic T. gondii expressing luciferase enabled real-time monitoring of an infection in vivo [ 6 ]. In addition, several reporter molecules have been generated for cytokines such as IFN-γ, IL-2, IL-10 and IL-12 to understand how their production can be visualized and their association with host cells in vivo ascertained [ 28 ]. There has also been recent progress in using real-time imaging of host-pathogen interactions, for example such approach has been reported in Toxoplasma , Plasmodium and Leishmania [ 29 ].

Toxoplasma gondii expressing fluorescent markers have been used to distinguish infected macrophages, uninfected macrophages and DCs. Such transgenic parasites are also used to characterise the immunological phenotypes of these cells under flow cytometry [ 30 , 31 ].

Another application for fluorescent marker-expressing parasites is the unravelling of the mechanisms leading to CM. For example, blood parasitemia and sequestration of parasites in the brain vasculature is the main predisposing factor for CM and both CD8 + and CD4 + T cells play important roles not only in the control of parasitemia, but also in the development of CM [ 32 ]. CD8 + T cells sequester in the brain tissue following P. berghei infection causing damage to the endothelial tissue of the brain through the production of perforins [ 33 ]. The association between Treg and CD8 + T cell recruitment in the pathogenesis of experimental CM was studied using P. berghei expressing luciferase and green fluorescent protein. Depletion of Treg cells with anti-CD25 monoclonal antibody leads to protection of mice from experimental cerebral malaria. In addition, the accumulation of parasites in the brain vasculature was reduced in these infected mice, resulting in a significant reduction of parasite burden. Mice lacking Treg cells showed higher numbers of activated CD4 + and CD8 + T cells in spleen and lymph nodes. However, CD8 + T cell recruitment to the brain was selectively reduced in these mice [ 34 ]. Thus, transgenic parasites have not only helped unravel the host’s immune response to wards the parasite but also the immune mechanisms contributing to a major aspect of the pathology of malaria.

Furthermore, a luciferase transgenic L. donovani has also been used to demonstrate a role for the Ras-related protein, Rab5, in the regulation of the phagosome-endosome fusion and how these subcellular compartments kill intracellular parasites [ 35 ]. Through expression of GFP in L. major , the temporal difference of the parasite antigens on the draining lymph node is demonstrated [ 36 ] and similar studies showed the role of lipophosphoglycan (LPG) in inducing DC-mediated pro-inflammatory responses using Leishmania mexicana LPG1 −/− mutants and this study reported high level of pro-inflammatory cytokine gene expression in the absence of LPG [ 37 ]. Therefore, the expression of reporter proteins by parasites has been important to track the events of parasite dissemination and replication during infection and such transgenesis technology has greatly increased the accessibility of improved humanized mouse models to investigate the protection efficacy of different parasite origin antigens, as discussed in the next section.

Expression of antigens from other parasite species

In order to show that particular antigens are important targets for antibody-mediated protection, transgenic parasites have become a very useful tool (Fig.  4 ). For example antibodies play a significant role in the inhibition of blood stage merozoites by targeting the major protein component of MSP-1 19 and therefore, by replacing the P. berghei allele with the P. falciparum one, MSP-1 19 antibodies with a high level of inhibitory potential against the human parasite, were generated in mice. As a result, during challenge trials, a positive correlation between protection of mice from the blood stage malaria and the level of the surface protein expressed was observed. Moreover, full-length protein variants have been expressed and characterized in a transgenic P. berghei lines and patent infection of mice by these transgenic lines showed production of protective antibodies [ 38 ].

Transgenic P. berghei parasite expressing a circumsporozoite protein induces a strong antibody production and protection efficiency. Briefly, the transgenic malaria parasite lines infect the RBC of C57BL/6 mice and leads to the activation of B cells and IFN-γ production by CD4 + T cells. Passive transfer of antibodies to naïve recipient mice confers protection through opsonization process

Plasmodium berghei , P. chabaudi and P. yoelii are three malaria species that infect mice and are most commonly used due to their shared pathological features with P. falciparum , the most pathogenic strains of human malaria parasite [ 39 ]. In order to investigate the potential of the circumsporozoite protein (CSP) as a vaccine antigen in vivo , the csp gene of rodent malaria parasites was replaced with the csp genes from human parasites such as P. falciparum and P. vivax . The chimeric rodent parasites could produce sporozoites in Anopheles stephensi mosquitoes, capable of infecting human and rodent hepatocytes [ 40 ]. Thus, by expressing recombinant antigens from a human parasite into a mouse parasite, it is possible to take advantage of a mouse model to identify neutralising immune responses in a mouse model and hence discover potential vaccine candidates for human malaria.

Expression of transgenes by parasites to improve their immunogenicity

Many parasites use immunomodulatory mechanisms to ensure their survival in the host by crippling the host’s immune response, most often through the production of immunomodulatory molecules [ 41 ], which bind or interact with host immune cells [ 42 ]. Others have developed ways of remaining silent by virtue of low or absent expression of pathogen associated molecular patterns (PAMPs). Thus, when parasites evade the immune system by suppressing expression of PAMPs, it might be possible to express PAMPs transgenes from other organisms, and hence attract the attention of the immune system to the parasite, making them more immunogenic. To unravel this issue, transgenic T. cruzi expressing an exogenous PAMP with the ability to activate the innate immune system such as (i) Salmonella typhimurium flagellin (FliC), (ii) Neisseria meningitidis (FAM18 strain) porin (PorB) or (iii) T. cruzi paraflagellar rod protein 4 (PAR4) genes have been generated. Not surprisingly, strong innate immune responses were observed when mice were infected with these transgenic parasites and the PAMPs activated innate immune cells and these activated immune cells played an important role in controlling T. cruzi infection [ 43 ]. These results suggest that a relative deficiency of PAMPs in T. cruzi helps the pathogen to survive in the host. These studies also showed that inoculation of exogenous PAMPs with T. cruzi and under continuous expression can induce strong CD8 + T cell responses which ultimately leads to the control and clearance of infection (Fig.  5 ). A similar study aimed at optimal immune control and clearance of parasites persisted in the host also showed that transgenic T. cruzi expressing flagellar protein PAR4 was more effective at inducing PAR4-specific CD8 + T cell responses, which improved protection during subsequent parasite challenges [ 43 ]. Hence, these experiments demonstrate that the relative absence of PAMPs in T. cruzi can be harnessed to study the importance of PAMPs from other sources, in the induction of adaptive immunity.

Expression of flagellar protein PAR4 in T. cruzi causes the activation of macrophages, CD8 + T cells and NKT cells which leads to the high rate of parasite destruction from the circulation through the production of different cytokines having direct effect such as TNF-a and through the activation of plasma cells and production of protective antibodies

The two functionally distinct T helper cell populations, which determine the Leishmania infections are the Th1 cells known for secretion of IL-2 and IFN-γ cytokines and Th2 cells known for the secretions of IL-4, IL-10 and IL-13. The susceptibility to Leishmania infection is associated with Th2 proliferation and secretion of their cytokine signatures mentioned above and resistance to infection is maintained by the secretion IFN-γ by CD4 + Th1 helper cells [ 44 ]. However, there is no clear evidence how the parasite skewed the immune response and leads into protection and disease progression. L. major secreting the mouse cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is engineered to induce protective host immune responses [ 45 ]. Indeed, GM-CSF induces secretion of many pro-inflammatory cytokines such as IL-1β, IL-18 and IL-6 by macrophages and, as a result, transgenic parasites expressing GM-CSF failed to survive. Transgenic Leishmania spp. engineered to produce monocyte chemoattractant protein 1 (MCP-1) were less pathogenic in susceptible BALB/c mice in vivo , with significant reduction in lesion size compared to wild-type parasites [ 46 ]. In addition, parasites producing MCP-1 caused CCR2 positive macrophage recruitment, but the innate immune response was less efficient at inducing protective immunity against subsequent challenges.

In another application, transgenic parasites can also be used as vaccine vehicles. Indeed, one study showed the development of a novel system for the expression of nematode secreted proteins in another parasite such as Trypanosoma musculi, a natural parasite of mice. Furthermore, acetylcholinesterase from Nippostrongylus brasiliensis was engineered in trypanosomes and these transgenic trypanosomes were able to induce a protective immune response against N. brasiliensis , by altering the cytokine environment. In the same study, immune cells exposed to acetylcholinesterase expressing parasites in vivo showed activation of macrophages, production of high levels of nitric oxide and decreasing arginase activity [ 47 ].

In summary, the transgenesis of proteins that improve immunogenicity of the parasite have given us insights not only in how parasites evade the immune system, for example by reducing the amount of danger signals they express but more importantly also in the fundamental mechanisms of immune regulation, particularly the role of key cytokines. Some of these engineered parasites might even be used as vaccine vehicles, although this would require passing considerable regulatory hurdles.

Deleting and knocking-down parasite genes to evaluate their effect on immune responses

Deletion mutants of parasites have been used to investigate the role of critical molecules in the binding of the parasite to the host cells and the effect of antibodies to these molecules in inhibiting this process. Indeed, studies in human malaria showed that erythrocyte binding-like (EBL) proteins and reticulocyte binding-like (RBL or PfRh) proteins are involved in erythrocyte bindings and are targets of human invasion inhibitory antibodies in addition to being important components of acquired protective immunity [ 48 ]. A construct of P. falciparum lines in which eba-175 , eba-181 , and eba-140 genes were knocked out by targeted disruption, showed that the EBL and PfRh proteins functionally interact during merozoite invasion. Further evidence showed that PfRh and EBL proteins induced antibodies that potently blocked merozoite invasions and hence these antigens could potentially be used as vaccine candidates [ 48 , 49 ]. The targeted disruption of key genes to establish a role for antibodies to specific proteins can only be used when knock-out parasites are viable, as is the case with the eba genes. However, in some instances such as the MSP-1 protein a knock-out strategy can be unsuccessful [ 50 ], for example if the protein is essential for parasite survival. In such cases researchers have resorted to the more complex approach of expressing the protein from one species of malaria into another (see below), to demonstrate the role of antibodies in protection. Another alternative is the use of RNAi, which by its nature downregulates the expression of the protein but does not abolish expression altogether.

The ability of parasites to modulate immune responses is often mediated by the production of immunomodulatory molecules. Hence, there is a growing interest in the characterization of the mediators released by the parasites and analysing how such molecules can redirect the host’s immune response [ 42 ]. This might also have a tremendous advantage in developing unique and targeted therapies not only against the parasites [ 51 ], but also potentially for the treatment of other immune-mediated conditions.

Parasites, such as Schistosoma mansoni , are among the pathogenic organisms that invade diverse organ systems such as the lymphatic system, the gastro-intestinal tract and the vascular system with multiple immunomodulatory lines of attack on the immune system. Co-evolution of parasites and their hosts’ immune system has resulted in a delicate balance that allows chronic infections to be maintained without provoking fatal immunopathology or overwhelming infection in the host [ 52 , 53 ]. S. mansoni egg proteins including Omega-1, IPSE, and kappa-5 are the main contributors of egg-induced immune regulation [ 54 ]. The effect of soluble egg antigens (SEA), such as Omega-1 , is attributed to an altered interaction of DCs with Th cells and the initiation of mRNA and rRNA degradation. This leads to abolished protein-expression by DCs. These interactions and the immunomodulatory mechanisms can be investigated by downregulating Omega-1 in S. mansoni eggs and studying the effect in vivo [ 8 ]. Omega-1 alone can induce a Th2 response in vitro and in vivo through the conditioning of DCs. Indeed, the depletion of this protein totally abrogates the maturation of T cells induced by schistosome SEA in vitro [ 55 ]. As mentioned in the introduction, multicellular parasites are difficult to transfect using classical molecular techniques and of the require lentivirus-mediated transgenesis. Lentiviral transduction system mediated knocking-down of Omega-1 in S. mansoni eggs leads to the production of IFN-γ [ 8 ] (Fig.  6 ). In the same study, lung cell suspensions from naïve mice, which were intravenously injected with wild-type and empty vector transduced S. mansoni eggs revealed a characteristic Th2 cytokine profile (IL-4, IL-5, IL-6, IL-10 & IL-13) with low levels of Th1 (IL-1α, IL-12, INF-γ, TNF-α), and Th17 cytokines (IL-17, IL-22). Moreover, intravenous injection of wild-type S. mansoni eggs increased numbers of eosinophils, granulocytes, T helper cells, alveolar APCs and B cells [ 8 ]. In contrast, mice injected with Omega-1 knock-down eggs had a cytokine profile characterised by a slight increase in Th1 cytokines, such as TNF-α. However, no significant difference in the levels of Th1, Th2, and Th17 cytokines was observed between the Omega-1 knock-down eggs and wild-type or the empty vector controls. However, Omega-1 knock-down parasites had reduced pathology in the lungs, suggesting an effect on granuloma formation. Although Omega-1 is the principal component of SEA, which conditions DCs for priming Th2 responses, it is not the only glycoprotein in SEA that can induce these responses. Other egg proteins, such as IPSE and Kappa-5 also play a role in immunomodulation of the host’s immune response. Hence, knock-down of Ipse and Kappa-5 leads to a slight decrease in IL-2 and IL-10 production and an increase in secretion of IL-1 and IL-6 but, the overall difference in the level of secreted cytokines was not significant for either of the SEA knock-down groups.

Schistosoma mansoni eggs transduced with lentiviruses containing shRNAmir showed a significant reduction the size of granuloma comparing with the untraduced eggs [ 8 ] and the expression of chicken ovalbumin in S. mansoni eggs after delivery of the OVA transgene through the lentiviral transduction system leads in to the recognition of the OVA by OT-II T cells in vitro

In recent years the CRISPR/Cas9-based genome edition tools have become a standard way of disrupting key genes in order to study their effect. However, most of the studies so far have used this technique to investigate the parasite biology rather than host-parasite interactions, which fall outside of the scope of this study. While one can expect many future studies to include CRISPR/Cas9-based genome edition tools in the study of immune responses to parasite, the only study so far targeted Omega-1 of S. mansoni eggs and the results conformed these discovered by downregulating this gene using the RNAi/lentiviral transduction system, namely a reduction of pulmonary granuloma [ 56 ].

In another parasite example, deletion of L. mexicana cysteine peptidase B in these parasites resulted in similar lesion-development compared to wild-type parasites in the early stages of infections [ 57 ]. However, mice infected with CPB -/- parasites cleared the infection after inducing a STAT4 and IL-12-dependent Th1 response, indicating that cysteine peptidase B suppresses the immune response [ 58 ].

Finally, disruption of the conserved 6-Cys B gene family, which plays a role during development of sexual stages of Babesia bovis, resulted in inhibiting parasite invasion of red blood cells [ 59 ]. Such novel gene manipulation approach could generate attenuated parasites usable as vaccines against babesiosis.

Taken together these experiments demonstrate the usefulness of different gene-disruption and downregulation technologies for the study of gene function of parasites including these highlighted here in relation to host-parasite interactions. While gene disruption offers a more absolute effect because the protein of interest is completely absent, gene downregulation has the advantage that if the gene is essential the parasite might survive although in an impaired state and hence an effect might still be observable in that case.

Summary and future directions

As outlined in this review, recent advances in transgenesis of complex parasites have allowed significant progress towards understanding the immunobiology of a range of parasites. These advances could potentially also be applied to even larger parasites, such as parasitic nematodes. Indeed, the tracking of nematode-specific T cell responses has so far been a challenge [ 60 ]. The use of nematodes expressing model antigens, such as OVA, might help in this respect, particularly if combined with T cell receptor transgenic mice. Studies over the last two decades involving in vivo depletion of specific cells, cytokines and their receptors showed that the immune response to nematodes in a murine model is mainly dependent CD4 + T cells [ 61 , 62 ]. Parasitic nematodes induce immunomodulatory mechanisms to invade their host and sustain their infectivity [ 63 ]. While there is a general mechanism of immunomodulation by nematodes which involves the release of molecules capable of manipulating host immune responses, the nature, and mechanisms of altering the host’s immunity is different from one parasitic nematode to the other [ 41 ]. Therefore, to help with this endeavour knock-down or deletion of specific genes suspected to have effects on the immune system can be generated and used to confirm their respective roles.

Importantly, parasites in which one key immune mechanism has been eliminated could potentially reveal additional mechanisms that are normally masked by the overpowering effect of the main immune mechanism. The use of transgenic parasites in studying immune response is summarised in Table  1 . Therefore, we forwarded the following learning points.

We have reviewed current advances focusing on the use of transgenesis as a tool in the study of host-parasite interactions.

The transgenesis approach is now becoming a novel technique in the integration of foreign genes reliably into the host genome for functional analysis of the immune response in vivo .

To date, few transgenic parasites have been developed and improvements in the advancement of this field is required to increase our knowledge of parasite immunology.

We foresee that such advancement in transgenesis technology could pave the way to rapid developments in functional genomics as it relates to host-parasite interactions. For example, high throughput insertional mutagenesis, expansion of RNAi for in vivo studies might soon become a practical reality.

We also expect the advances achieved thus far can be adapted in a wide range of pathogenic parasites to understand their nature of interaction with the host.

Conclusions

In conclusion, transgenic parasites have been utilised in a wide range of applications to investigate complex host-parasite interactions in vivo . Indeed, using this versatile technology, it is now possible to unravel the detailed immune response to parasites. While this review highlights how transgenic parasites have influenced our understanding of the host-parasite interaction, many additional questions remain and establishing these advanced transgenesis methods for applications in an ever-increasing variety of parasite species will undoubtedly result in the discovery of fascinating insights about the interactions of parasites with the immune system of their hosts.

Availability of data and materials

Not applicable.

Abbreviations

RNA interference

T cell receptor

major histo compartment I

major histo compartment II

dendritic cells

cerebral malaria

parasitophorous vacuole membrane

lipophosphoglycan

chicken ovalbumin

circumsporozoite protein

merozoite surface protein

pathogen-associated molecular pattern

soluble egg antigens

messenger RNA

ribosomal RNA

granulocyte-macrophage colony-stimulating factor

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Tedla, M.G., Every, A.L. & Scheerlinck, JP.Y. Investigating immune responses to parasites using transgenesis. Parasites Vectors 12 , 303 (2019). https://doi.org/10.1186/s13071-019-3550-4

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Combating Parasites: Immune Response and Inflammation

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An organism’s physiological equilibrium is critically reliant on its immune system, which provides protection against parasites, pathogens, toxic substances, and cancerous cells and allows recovery from injuries. The immune response is, however, not cost free. It demands various kinds of resources, but also more subtle costs. In the last couple of decades, there has been growing interest by ecophysiologists and evolutionary ecologists in the investigation of oxidative stress as a potential cost of immune activation and induction of anti- and pro-inflammatory mechanisms. A core idea of the immuno-oxidative ecology is that oxidative stress may provide a currency to quantify physiological costs that impinge on growth, reproduction or senescence. This chapter deals with such research and also examines how exposure to mild stress may stimulate activity of immune cells through hormetic mechanisms.

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Costantini, D. (2014). Combating Parasites: Immune Response and Inflammation. In: Oxidative Stress and Hormesis in Evolutionary Ecology and Physiology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54663-1_8

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Helminth Parasites' Regulation of Host Immune Response Reduces Inflammatory Disease Symptoms

New information about how helminths regulate their hosts’ immune system may provide valuable insight for therapies to fight inflammatory diseases.

Helminths (namely, cestode tapeworms, nematode roundworms, and trematode flukes) are long-lived worm parasites that have evolved methods to dampen the host’s immune response, protecting the parasite from elimination by the host, and minimizing severe disease in the host. In a recent review article , in the Journal of Allergy and Clinical Immunology, Rick M. Maizels, PhD, from the University of Glasgow, Scotland, and Henry J. McSorley, from the University of Edinburgh, Scotland, discuss some of immunomodulatory mechanisms associated with helminth infections, how they apply to human disease, and possible areas for future research.

Helminths and the Immune System

Helminths are very successful parasites and their success results from their active regulation of the host immune response. Although only about a dozen helminth species are widespread in humans, together they infect almost one-third of the world’s population—often for up to 20 years. “Their extraordinary prevalence bears witness to their success at defeating host defences,” the authors write. This reflects their ability to manipulate the host’s immune system and dampen responses that could eliminate them. Studies have shown the ability of helminths to induce, modulate, or suppress certain pathways of immune activation in the host.

Induction of T helper (Th) type 2 immune responses with a regulatory component is a classic host response to helminth infections, and dendritic cells play a key role in this induction. Although exactly how these cells recognize the presence of helminths remains unknown, KLF4 factor is an essential intracellular signal that allows dendritic cells to promote Th2 responses.

A critical link has also emerged between helminth infection and increased production of regulatory cells, especially regulatory T cells (Tregs)—including those expressing the transcription factor Foxp3—that block protective immune responses. These cells are essential to allow helminths to survive in the host and avoid being expelled, but evidence shows that they may also protect the host from pathology. Helminth-induced regulatory B cells (Bregs) also play an important role in modulating the immune response during helminth infection. Emerging evidence also suggests that these cells can suppress allergic inflammation. “Along with Treg[s], Bregs are strongly implicated in the development of tolerance to allergens and strategies to encourage their expansion could increase the efficacy of allergen-specific immunotherapy,” the authors write.

Helminths can effectively modulate the adaptive immune response to enable them to survive in the host. For example, they can promote Treg differentiation, either directly by producing a TGF-β-like mimic or indirectly by inducing host TGF-β and retinoic acid (RA) production by dendritic cells and macrophages. This allows the parasites to hijack the host’s TGF-β signaling pathway, suppress the host’s protective Th2 response, and thereby avoid immune attack.

Suppression

Helminths suppress some key pathways of immune activation in the host. For example,

when helminths cause tissue damage during infection, they trigger release of alarmin cytokines, including interleukin 33 which activates innate lymphoid cells that promote development of the type 2 response against the helminths; the parasites also inhibit toll-like receptor (TLR) responses of dendritic cells. However, with repeated infection, the host’s immune responses are dampened: helminths can effectively block alarmin production and TLR function, ultimately preventing the T helper (Th) type 2 immune response.

Allergy, Autoimmunity, and Allograft Rejection

Helminth-induced immunomodulation can be beneficial for the host, as well as the parasite. “It has been noted since 1968 that inflammatory disorders such as arthritis are much less frequent in low-income countries with high levels of parasite infection,” the authors note. And regions of the world where helminth parasites are endemic have a lower prevalence of allergies and autoimmune conditions—as well as increases in allergic reactivity and autoimmune antibodies after anthelmintic treatment. According to the authors, helminths probably affect the immune system at two levels—by modifying the level of host reactivity during development of the immune system during infancy, and by suppressing immune responses in mature individuals who may be exposed to helminths for the first time in adulthood. “It is the latter setting that led to the proposal that helminths or their products could be used as therapies for inflammatory diseases in the parasite-free developed world,” they say. Similarly, evidence is mounting to suggest that helminth infections may protect against allograft rejection in transplant recipients.

Future Directions

The authors also stress that increased understanding of immunosuppressed responses to helminths, and of how to neutralize these responses, may improve understanding of anti-cancer responses. “Parasitic infection could increase carcinogenesis through associated low-grade chronic inflammatory response (in the absence of parasite ejection), secretion of directly pro-carcinogenic factors, or suppression of immune surveillance,” they state. “Epidemiological data in this area is presently lacking, and the effects of parasitic infection in cancer progression requires further attention.

“As we discover more about how productive anti-parasite responses are produced, we are also discovering new pathways for immunomodulation of these pathways by helminth infections, and exploring new possibilities for exploiting parasite molecules as therapies for inflammatory diseases,” the authors conclude.

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.

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Immunology of lymphatic filariasis

Subash babu.

1 NIAID-NIRT-ICER Chennai India

Thomas B. Nutman

2 Helminth Immunology Section Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases Bethesda, MD 20892-0425

The immune responses to filarial parasites encompass a complex network of innate and adaptive cells whose interaction with the parasite underlies a spectrum of clinical manifestations. The predominant immunological feature of lymphatic filariasis is an antigen - specific Th2 response and an expansion of IL-10 producing CD4 + T cells that is accompanied by a muted Th1 response. This antigen specific T cell hypo-responsiveness appears to be crucial for the maintenance of the sustained, long-standing infection often with high parasite densities. While the correlates of protective immunity to lymphatic filariasis are still incompletely understood, primarily due to the lack of suitable animal models to study susceptibility, it is clear that T cells and to a certain extent B cells are required for protective immunity. Host immune responses, especially CD4 + T cell responses clearly play a role in mediating pathological manifestations of LF, including lymphedema, hydrocele and elephantiasis. The main underlying defect in the development of clinical pathology appears to be a failure to induce T cell hypo-responsiveness in the face of antigenic stimulation. Finally, another intriguing feature of filarial infections is their propensity to induce bystander effects on a variety of immune responses, including responses to vaccinations, allergens and to other infectious agents. The complexity of the immune response to filarial infection therefore provides an important gateway to understanding the regulation of immune responses to chronic infections, in general.

Introduction

Lymphatic filariasis is an infection caused by three closely related nematode worms – Wuchereria bancrofti, Brugia malayi and Brugia timori . The parasites are transmitted by mosquitoes and their life cycles in humans consists of adult worms living in the afferent lymphatic vessels while their progeny, the microfilariae, circulate in the peripheral blood. Although typically clinically asymptomatic, lymphatic filariasis can also be associated with lymphatic disease, which is responsible for considerable suffering, deformity and disability and is the second leading parasitic cause of disability with DALYs (disability-adjusted life years) estimated to be 5.549 million ( 1 ). Bancroftian filariasis, caused by W. bancrofti is responsible for 90% of those with lymphatic filariasis ( 2 ) and the rest are caused by Brugian parasites. Lymphatic filariasis is a global health problem. At the present time (2013), the World Health Organization estimated that over 1.25 billion people are at risk in 72 countries and territories. It is known that approximately 120 million people infected with lymphatic filariasis and over 40 million have pathologic consequences, including the disfiguring elephantiasis. Clinical disease is manifested primarily as acute adenolymphangitis and chronic lymphedema that may lead to elephantiasis in men and women and to the formation of hydroceles (for W. bancrofti at least) in men.

All human filarial nematodes have a complex life cycle involving an insect vector, with Wuchereria and Brugia being transmitted by mosquitoes. Infection begins with the deposition of infective larvae (L3) in the skin during a mosquito bite. The larvae then enter through the puncture wound, reaching the lymphatics and migrate towards the lymph nodes. They reside within the lymphatics and lymph nodes and undergo a process of molting and development to form L4 larvae and then adult worms. Following mating the adult female releases live progeny called microfilariae that circulate in the bloodstream. These microfilariae can then be ingested by a mosquito during a subsequent blood meal, where in they undergo development to form L2 and finally L3 larvae. The complex life cycle engenders a complicated host immune response, and it is this complexity of the host-parasite interaction that is thought to underlie the varied clinical manifestations of lymphatic filariasis. Lymphatic filariasis can manifest itself in a variety of clinical and subclinical conditions ( 2 ). The most common clinical manifestation is a relatively asymptomatic or subclinical infection characterized by the presence circulating microfilariae and the relative absence of clinical symptoms. A subgroup of individuals present clinically with overt pathology in the form of lymphedema, hydrocele and elephantiasis. In this review, we discuss mostly studies pertaining to human filarial infections and have used the Brugia infection of mice as the primary model for studying host immune interaction with filarial parasites and referred to the Litomosoides model only in the absence of data from the Brugian model.

Prototypical immune responses

The canonical host immune response to filarial parasites in both mice and humans is of the T helper 2 (Th2) type and involves the production of cytokines – IL-4, IL-5, IL-9, IL-10 and IL-13, the antibody isotypes – IgG1, IgG4 (in humans) and IgE, and expanded populations of eosinophils and alternatively activated macrophages ( 3 ). The initial interaction of T cells with a variety of host cell types including dendritic cells and macrophages induces and culminates in Th2 responses ( 3 ). While dendritic cells, basophils and innate lymphoid cells have been all shown to initiate Th2 responses in other helminth infections, their role in the initiation of early Th2 responses in filarial infections is still unclear. Type 2 innate lymphoid cells (ILCs) have been shown to be important players in the initiation of Th2 responses in helminth infections ( 4 , 5 ). Recent data from our lab has shown that ILC2 are expanded in both mouse models and human filarial infections and produce copious amount of IL-5 and IL-13 at times preceding the onset of classical Th2 responses (unpublished results). Thus, ILC2 might be important players in orchestrating the establishment of the Th2 response in filarial infections. These prototypical Th2 responses are modulated by both adaptive and natural regulatory T cells, alternatively activated macrophages, eosinophils and other cell populations over the duration of infection ( 6 ). The main characteristic of a chronic filarial infection appears to be the presence of a modified Th2 response and an IL-10 dominated regulatory environment ( 6 ).

T cells are the key players in immunity to filarial infections. Both nude mice (that lack T cells) ( 7 , 8 ) and SCID or Rag-deficient mice (that lack both T and B cells) ( 9 , 10 ) are susceptible to infection with Brugian parasites, indicating that T cells are absolutely critical for elimination of infection. It appears, however, that either T cell subset - CD4 + or CD8 + T cells - can mediate resistance in non-permissive animals since mice that lack either CD4 + T cells or CD8 + T cell are fully capable of resisting infection ( 11 , 12 ). In addition, protective immunity to filarial infections in mice is dependent primarily on Th2 responses in mice. Thus, mice lacking IL-4, IL-4R or Stat6 (all deficient in Th2 responses) are all susceptible to infection with Brugia parasites ( 13 , 14 ). Interestingly, IFNγ also appears to play an important role in protection against infection since mice lacking IFNγ, exhibit impairment in the elimination of the parasite ( 13 ). Therefore, protective immunity to filarial infections requires co-ordination of both Th1 and Th2 responses.

One of the most consistent findings in filarial infections is the elevated level of IgE that is observed following L3 exposure ( 15 ). Most of the IgE produced is polyclonal IgE indicating a non- antigen specific induction of IgE producing B cells. ( 16 ). Indeed, these IgE antibodies remain detectable many years after the infection has been treated indicating the presence of long lived memory B cells or plasma cells in filarial infections ( 17 ). IgE production both in mice and humans is absolutely dependent on IL-4 or IL-13. Other isotypes that are commonly elevated in chronically filarial - infected humans are IgG4 and IgG1, the former being most dependent on both IL-4 and IL-10 ( 18 ). The role of B cells in resistance to infection is less clear, although B cells. especially a specialized subset of B cells called B1 B cells, also appear to exert a major role in resistance to infection ( 19 ). Antibodies do play a major role in mediating protection to filarial infections. Thus, in vivo data from mice deficient in IgE, showed increased worm burdens with B. malayi indicating an important role for IgE in host defense ( 20 ). Again using knockout mice models, IgM has also been shown to be crucial for host protection against B. malayi ( 21 ). In the lymphatics and lymph nodes as well as in the circulation, filarial parasites are susceptible to attack by the full range of host innate effector cells, including macrophages, eosinophils and neutrophils. The ability of these cells to kill the parasites is often dependent on one or more isotypes of specific antibody (often IgE but also IgM) and complement. Activated macrophages or granulocytes can release nitric oxide, damaging nitrogen intermediates and reactive oxygen species onto the surface of the parasites, but in vivo killing methods are not yet fully understood.

Dendritic cells are professional antigen-presenting cells that play an essential role in presenting antigen to T cells to initiate immune responses, yet their role in filarial infections is not fully understood. It has been shown that differentiation and maturation of DC in the presence of filarial antigens in vitro can stimulate Th2 responses with downmodulation of IL-12 production ( 22 ). In addition, live parasites have also been shown to induce cell death in human dendritic cells and diminish their capacity to activate CD4 + T cells ( 22 ). Finally, asymptomatic filarial infection is characterized by increased numbers of circulating myeloid dendritic cells (defined as Lineage − , HLA-DR + , CD11c + cells) ( 23 ). On the other hand, human Langerhans’ cells (langerin(+) E-cadherin(+) CD1a(+)) exhibit minimal alterations in the cell surface activation markers or in mRNA expression of inflammation-associated genes, indicating a quiescent initial interaction of the parasite with human epidermal LC ( 24 ).

Macrophages are the other important class of antigen presenting cells that can serve as protective effector cells in bacterial and protozoan infections by their production of nitric oxide and other mediators. A special class of macrophages are known to be induced in filarial infections, characterized by their preferential expression of the enzyme arginase, instead of nitric oxide due to increased activation of arginase-1 by IL-4 and IL-13 ( 25 ). These macrophages, termed alternatively activated macrophages, have a very specific gene expression profile, with the ability to upregulate markers including arginase-1 , chitinase 3-like proteins 3 and 4 (also known as YM1 and YM2 , respectively) and resistin-like molecule-α (RELMα) ( 26 ). These alternatively activated macrophages are known to be important in wound healing and are thought to help limit tissue immunopathology ( 27 ). By virtue of expression of expressing regulatory molecules such as IL-10, TGFβ and programmed cell death 1 ligand 2 (PDL2), these macrophages might play a predominantly regulatory role in filarial infections ( 27 ). Interestingly, these filarial induced macrophages appear to have the ability to expand locally and are less dependent on influx of monocytes from the bloodstream to perform their functions( 28 ). While filarial infection does induce expression of these cells in humans, early interaction of parasites or parasite antigens leads to a predominantly pro-inflammatory response with expression of mainly pro-inflammatory cytokines including TNFα, IL-6 and IL-1β, as well as genes involved in inflammation and adhesion ( 29 ). Studies from murine models of filarial infection and in vitro data indicate that nitric oxide production by macrophages might be a key lethal hit in the host defense against the parasite ( 30 ). Therefore, the induction of alternatively activated macrophages might be an important immune evasion strategy for the parasites. Indeed, monocytes from patients with asymptomatic filarial infection also exhibit hallmarks of alternative activation, with diminished expression of inducible nitric oxide and enhanced expression of arginase-1 , along with increased expression of resistin, mannose receptor C type 1 (MRC-1), macrophage galactose type C lectin (MGL) and chemokine ligand 18 (CCL18). Interestingly, live filarial parasites induce a monocyte phenotype that partly resembles the alternatively activated state seen in infected individuals ( 31 ). Finally, monocytes, especially classical monocytes, appear to be remarkably efficient in antigen-uptake in filarial infections ( 32 ).

Blood eosinophilia is characteristic of filarial infection and is mediated by IL-5 (probably in concert with IL-3 and GM-CSF) ( 33 ). Eosinophils are often the first cell type recruited to the site of infection and eosinophilia occurs characteristically early following infection ( 33 ). Apart from the rapid kinetics of recruitment, eosinophils also exhibit morphological and functional changes attributable to eosinophil activation. These include changes in cell density, increased surface expression of activation markers, enhanced cellular cytotoxicity and release of granular proteins, cytokines, leukotrienes and other mediators of inflammation ( 33 ). Basophils have gained prominence recently due the possible role in Th2 cell differentiation as providers of initial IL-4 and even antigen-presenting cells (APCs). Basophils in humans and mice readily generate large quantities of IL-4, in response to various stimuli, including filarial antigens, with or without dependence on IgE ( 34 ). In murine filarial infections, effector mechanisms involve multiple innate immune cells, with antibodies acting as initiators of immunity by activating Fc receptor expressing cells. Basophils, by their ability to produce high levels of IL-4, act as effectors to promote filarial killing in secondary or challenge infections ( 35 ). Although eosinophils are crucial contributors to the early IL-4 pool, they are also important in protection against primary filarial infections ( 36 , 37 ). The mechanism of protection mediated by eosinophils is thought to antibody-dependent cell mediated cytotoxicity or through release of eosinophil granule contents.

Immune evasion

Filarial parasites exert profound immunoregulatory effects on the host immune system with both parasite-antigen specific and more generalized levels of immune modulation. The main mechanisms of immune evasion include immunosuppression, immunological tolerance and modification of stereotypical Th2 responses ( 3 ). Immunosuppression and immunological tolerance are characterized typically by immunoregulatory cytokine induced suppression of immune responses and a state of immune tolerance in effector T cells, respectively. On the other hand, in the modified Th2 response, antibody isotype switching to the non-inflammatory isotype IgG4 (in humans) and induction of alternatively activated macrophages occurs ( 3 ). It has been shown that patients with lymphatic filariasis have markedly diminished responses to parasite antigens and in addition, some non-specific inhibition of responses to bystander antigens ( 38 ). Thus, while host immunosuppression is usually antigen-specific, chronic infection is often associated with spillover effects on third party antigens as well.

Among the notable immune-evasion strategies, a key one is the secretion of products that modulate host immune function. Phosphorylcholine (PC) is a small hapten-like moiety present in the excretory/secretory products of many helminths and one particular PC containing molecule called ES-62 from filarial worms has been shown to have a wide variety of immunomodulatory properties ( 39 ). Thus, ES-62, can downregulate the proliferation of CD4+ T cells and conventional B cells, decrease IL-4 and IFNγ production, upregulate proliferation and IL-10 production by B1 B cells and condition antigen-presenting cells to drive Th2 differentiation with concomitant inhibition of Th1 responses ( 40 ). Similarly, the presence of cytokine and chemokine like molecules in filarial parasites has been shown to have functional effects on the host innate immune responses as is the case with TGFβ and macrophage migration inhibitory factors (MIF) homologs ( 41 ). In addition, a recent analysis of the filarial parasite genome has identified a remarkable number of human cytokine and chemokine mimics and/or antagonists within the parasite genome. These include members of the interleukin-16 (IL-16) family, an IL-5 receptor antagonist, an interferon regulatory factor, a homolog of suppressor of cytokine signaling 7 (SOCS7) and two members of the chemokine-like family. Moreover, other potential immunomodulators have been demonstrated to be present in the filarial genome, including serpins and cystatins (modulation of antigen processing and presentation to T cells), indoleamine 2,3-dioxygenase (IDO) genes (potent immunomodulatory molecule), and Wnt family of developmental regulators (modulation of immune activation)( 42 ).

The induction of regulatory T cells, modulation of effector T cell and antigen-presenting cells and apoptosis of responder cells ( 43 ) have been suggested to be the major factors influencing the regulation of the immune response in filarial infection. Regulatory T cells (both natural and adaptive) have been postulated to play a role in the immune evasion mechanism of the parasite. IL-10 and TGFβ, both factors associated with regulatory T cells, are elicited in response to helminth infections, and in vitro neutralization of IL-10 and TGFβ has been demonstrated to partially restore both T cell proliferation and cytokine production in lymphatic filariasis ( 44 ). Similarly, evidence from mouse models argues for a major role of natural Tregs (CD25 + Foxp3 + Treg cells) in immunity during filarial infections ( 45 - 47 ). In murine filarial infections, parasite survival is directly linked to Treg activity and immunity to infection can be restored by elimination of Tregs ( 45 ). Effector T cell responses can be turned off or modulated through a variety of mechanisms including through CTLA-4 and PD-1. Interestingly, increased expression of CTLA-4 and PD-1 has been demonstrated in human filarial infections, and blocking of CTLA-4 can restore partially a degree of immunological responsiveness in cells from infected individuals ( 48 , 49 ). Similar findings have also been observed in murine models of filarial infection ( 50 ). Finally, classical signs of anergy has been demonstrated in T cells of filarial infected individuals with decreased IL-2 production and increased expression of E3 ubiquitin ligases ( 49 ).

Filarial parasites induce downmodulation of MHC class I and class II as well as cytokines and other genes involved in antigen-presentation in dendritic cells, thereby rendering them less capable of activating CD4+ T cells ( 22 ). In addition, live parasites have also been shown to cause downregulation of MHC class II and IL-8, I and multiple genes involved in antigen presentation in skin-resident LC ( 51 ). Filarial parasite interaction with macrophages has been shown to induce alternatively activated macrophages. By virtue of expression of expressing regulatory molecules such as IL-10, TGFβ and programmed cell death 1 ligand 2 (PDL2), these macrophages may also have a predominantly regulatory role in filarial infections ( 52 ). These anti-inflammatory macrophages can suppress T cell responses through arginase-1 production and PDL2 expression and inhibit classical macrophage inflammation and recruitment through arginase-1, RELMα, triggering receptor expressed on myeloid cells 2 (TREM2) and other molecules ( 53 ). Another mechanism of immune evasion is the ability of filarial parasites to induce host cell apoptosis ( 54 ). Apoptosis of CD4+ T cells has been demonstrated in vivo in experimental models of filarial infection in mice. In addition, Brugia microfilariae have been shown to interact with dendritic cells and NK cells and subsequently induce their apoptosis ( 22 , 55 ).

One of the main characteristics of asymptomatic or subclinical filarial infection is the modulation of TLR expression and function in a variety of cell types including B cells, T cells and monocytes ( 56 , 57 ). Either homeostatic or antigen-stimulated expression of certain TLRs was shown to be diminished in B cells, T cells and monocytes of filarial-infected individuals. In addition, TLR stimulation of both APCs and T cells leads to diminished activation / cytokine production, indicating a state of immune regulation. Furthermore, live filarial parasites have the capacity to downregulate TLR expression (specifically TLR3 and 4) on dendritic cells as well ( 58 ). This is accompanied by an impaired ability of dendritic cells to produce certain cytokines in response to TLR3 and 4 ligands. The diminished expression and function of TLR on immune cells is thought to be a likely consequence of chronic antigen stimulation and probably serves as a novel mechanism to protect against the development of pathology in filarial disease ( 59 ).

While most of the immunological studies in filarial infections have focused on filarial antigen induced immune responses, the study of the immune responses engendered by live parasites provides some interesting details ( 49 ). Live parasites cause a significant impairment of both Th1 and Th2 cytokines in response to both L3 and Mf stages with diminished production of Th1 (IFNγ and TNF-α) and Th2 ( IL-4 and IL-5) cytokines. This is accompanied by an impaired induction of T-bet (the master Th1 transcription factor) and GATA-3 (the master Th2 transcription factor) mRNA and by significantly increased expression of Foxp3, TGFβ, CTLA-4, PD-1, ICOS and IDO. In addition, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors – cbl-b, c-cbl, Itch and Nedd4. Finally, blocking CTLA-4 or neutralizing TGFβ restored the ability to mount Th1/Th2 responses and reversed the induction of anergy-inducing factors. Thus, a variety of regulatory factors including IL-10, TGFβ, nTregs (perhaps via PD-1 and CTLA-4) have been implicated in the downmodulation of immune responses in patent filarial infection and might have a potentially vital role in the establishment of chronic, asymptomatic infection.

Pathogenesis of filarial disease

The most severe clinical manifestations of lymphatic filariasis are lymphedema and elephantiasis. The first major insights into the role of lymphatic damage in the pathogenesis of lymphatic filarial disease came from studies using Brugian infections of animals. Infection of normal or nude (lacking T cells) mice resulted in lymphangitis and peri-lymphangitis in both groups of mice with acute and chronic inflammation predominating in the former ( 60 ). Interestingly, since normal mice are not permissive to infection, lymphangiectasia was observed to progress only in nude mice. While infection of nude mice was characterized predominantly by lymphangiectasia, reconstitution of these mice with spleen cells from normal mice (thereby restoring normal adaptive immunity) resulted in progressive fibrosis, obliterative lymph thrombus formation, interstitial infiltrates and extensive perilympangitis ( 61 ). Similarly, studies using SCID mice (lacking both T and B cells) showed that lymphangitis and lymphangiectasia were classical features of infection in the absence of adaptive immunity, and that reconstitution with spleen cells from normal mice resulted in progressive disease ( 9 ).

Pro-inflammatory cytokines of innate origin also appear to play an important role in brugian infection since infection of nude mice results in elevated levels of IL-1, IL-6, TNF-α and GM-CSF in lymph fluid ( 62 ). Therefore, innate cytokines appear to play a prominent role in the initiation of pathology in filarial-infected animal models. The importance of pro-inflammatory cytokines, possibly of innate origin, in the pathogenesis of lymphedema, has been further strengthened by a series of studies in humans in either the early or late stages or lymphedema. Studies have shown that individuals with chronic lymphatic pathology have elevated levels of C-reactive protein (an acute phase protein, indicating an acute inflammatory response), pro-inflammatory cytokines such as TNF-α, IL-6 and soluble TNF receptor, endothelin-1, IL-2, as well as IL-8, MIP-1α, MIP-1β, MCP-1, TARC and IP-10 in the peripheral circulation ( 6 ). Similarly, while patients with both acute and chronic manifestations of LF have elevated circulating levels of IL-6 and IL-8, only those with chronic disease manifestations have elevated levels of sTNF receptors ( 63 ). Another important mechanism of immune activation in chronic infections is the occurrence of microbial translocation with elevations in the circulating levels of microbial products. Microbial translocation across the intestine or across the lymphatics could possibly contribute to inflammation and innate immune activation. Indeed, we have shown that increased circulating levels of LPS (which serves as a marker for microbial translocation) and decreased levels of LPS-binding protein (LBP) are characteristic features of filarial lymphatic pathology ( 64 ). We have also demonstrated that this process is associated with development of an acute-phase response and the presence of markers of inflammation in plasma – CRP, alpha-2 macroglobulin, serum amyloid protein-A and haptoglobin ( 64 ). Moreover, increased serum levels of proinflammatory cytokines – IL-1β, IL-12, TNF-α and IL-6 are associated with progressive immune activation in filarial pathology. Since filarial lymphedema is known to be associated with increased bacterial and fungal loads in the lymphatics, we postulate that microbial translocation across the damaged lymphatics in filarial lymphedema is a novel source of immune activation.

Apart from systemic immune activation, progressive fibrosis and extracellular matrix remodeling is another salient feature of filarial pathology. Matrix metalloproteinases (MMPs) are proteolytic enzymes that control matrix remodeling and collagen turnover. These MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are produced by a variety of cell types including macrophages, granulocytes, epidermal cells, and fibroblasts. The dysregulation of MMPs and TIMPs is known to underlie the development of pathology in several infections, including viral, bacterial, spirochetal, protozoan, fungal, and parasitic infections. Along the same lines, recent data suggests that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process and that that altered ratios of MMP/TIMP are an important underlying factor in the pathogenesis of tissue fibrosis in filarial lymphatic disease. In addition, this is correlated with elevated levels of Type 2 cytokines known to be intimately involved in fibrosis – IL-5, IL-13 and TGFβ ( 65 ). Another study has also examined the alterations in pro-fibrotic factors in filarial pathology and revealed that increased levels of basic fibroblast growth factor (bFGF) and placental growth factor (PIGF) can also occur in filarial lymphedema patients ( 66 ). Thus, filarial pathology arises out of a complex early interplay between the parasite and the host's innate responses and its tissue homeostasis.

Studies in animals also implicate an important role for endothelial cells in pathogenesis of lymphatic dysfunction since these cells exhibit morphological alterations upon chronic infection. Indeed, live filarial parasites (and their excretory/ secretory products) induce activation, proliferation and tube formation in lymphatic endothelial cells ( 67 ). Moreover, only serum from patently infected or diseased individuals was shown to induce significant lymphatic endothelial cell (LEC) proliferation. This lymphatic remodeling recapitulates the observations seen in vivo in immunodeficient mice. Vascular endothelial growth factor (VEGF) family members have also been implicated in lymphangiogenesis. It was recently shown that lymphaticendothelial specific VEGF-C levels are significantly elevated in individuals with filarial disease ( 68 ). The other VEGF family member that has been implicated to play a role in filarial disease is VEGF-A ( 69 ). Elevated levels of VEGF-A and endothelin-1 have been observed in the serum of filarial-infected individuals and more specifically, VEGF-A has been implicated to play a role in the development of hydrocele due to its ability to induce increased vascular density, enhance leucocyte adhesion and promote lymphangiogenesis ( 70 ). Thus, excess secretion of pro-inflammatory cytokines and angiogenic factors like VEGF-A could result in extravasation and accumulation of fluids, plasma, and lymph from the blood and lymphatic vessels into the scrotum resulting in the formation of hydrocele. Other angiogenic factors such as angiopoietins-1 and 2 are also found at elevated levels in individuals with filarial-induced pathology ( 66 ).

In terms of cellular subsets, it was first discovered that individuals with chronic lymphedema have increased frequencies of activated CD8 + T cells (expressing HLA-DR) in the peripheral blood ( 71 ). Later, it was also shown that the frequency of CD8 + T cells in tissues (including skin and subcutaneous tissues) was increased as well ( 72 ). Indeed, biopsy specimens from affected tissues exhibited increased levels of VCAM-1, and PBMC supernatants from diseased individuals showed the capacity to up-regulate both MHC-Class I molecules and VCAM-1 on endothelial cell cultures ( 73 , 74 ). Moreover, TCR Vβ phenotyping revealed a biased TCR repertoire in the T cells infiltrating the affected tissues in diseased individuals ( 75 ). In addition, examination of chemokine receptor expression on T, B and NK cells revealed a significant increase in the frequencies of circulating CCR9 - expressing T and B cells ( 76 ). Since, CCR9 is not normally expressed on circulating T and B cells. these results suggest that chemokine receptors (particularly CCR9) are involved in the pathogenesis of lymphatic filarial disease and that trafficking of particular cellular subsets may influence clinical outcome. Unpublished data utilizing mutliparameter flow cytometry has failed to reveal any significant difference in the frequencies of circulating naïve, effector memory and central memory CD4 + and CD8 + T cells in patients with filarial disease compared to those with longstanding infection. Thus, alterations in T cell numbers and function, especially at the site of pathology, are probably of major importance in pathogenesis.

Using multi-color flow cytometry we have been able to show that the frequency of Th1 cells (CD4 + T cells expressing either IFNγ or IL-2 or TNF-α); Th9 cells (CD4+ T cells expressing IL-9 and IL-10); Th17 cells (CD4+ T cells expressing IL-17) and Th2 cells (CD4+ T cells expressing IL-22) is significantly enhanced in filarial pathology. This is accompanied by a concomitant decrease in the frequency of Th2 cells (CD4 + T cells expressing IL-4 or IL-5 or IL-13) both at homeostasis and following parasite antigen stimulation (data not published). Although less well studied than Th1 cells, Th17 cells might also have an important role in the pathogenesis of disease in filarial infection since PBMC from individuals with pathology (but not asymptomatic patients) express significantly higher levels of the Th17 associated cytokines as well as the master transcription factor - RORC at the mRNA level ( 77 ). Finally, pathology in lymphatic filariasis is also associated with expanded frequencies of Th9 cells, CD4 + T cells that express both IL-9 and IL-10 but not IL-4 and this frequency exhibits a positive correlation with the severity of lymphedema in filarial infections (unpublished results). Therefore, immunopathology in lymphatic filariasis appears to be mostly associated with poor regulation of effector CD4+ and CD8+ T cells that can unleash pro-inflammatory Th1, Th9 and Th17 type immune responses. How, these pro-inflammatory Th1, Th9 and Th17 cells interact with innate cells, endothelial cells and other target cells to initiate and propagate lymphatic damage and tissue fibrosis remains to be elucidated.

Conclusions

Filarial infections are a classic example of chronic infections in which complete elimination of all parasites is rarely achieved, presumably since sterilizing immunity might necessitate deleterious host immune responses. Therefore, immune-mediated pathology is often associated with disease manifestations in these infections. The optimal host response is one which balances parasite control at the levels in which the parasite load can be tolerated and maintenance of immune homeostasis without irreparable tissue damage. Filarial infections, for the majority of those infected, reflect immune system-parasite balance, a balance that, when it fails, results in significant immune-mediated inflammation and pathology. Interestingly, this is also reflected in the disease manifestations of the related filarial parasite, Onchocerca volvulus, where chronic, asymptomatic infection is associated with loss of parasite control and the hyper-reactive, pro-inflammatory state is associated with severe chronic papular dermatitis and hyperpigmenation (sowda) ( 78 ).

Regulation of the immune responses in filarial infections. The complex outcome of the interaction between the filarial parasite and the host immune system determines the immunological outcomes including: (a) protection against infection; (b) parasite specific T cell hypo-responsiveness and alteration of APC function; (c) chronic infection; (d) protection against pathology and (e) anti-inflammatory bystander suppression.

Acknowledgements

This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Conflict of Interest Disclosure

Because S. Babu and T. B. Nutman are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license.