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The "Old Friends Hypothesis" suggests insufficient exposure to symbionts hinders immune development, contributing to increased immune-related diseases in the Global North. The microbiome is often the focus; helminths, potentially also offering health benefits, lack attention. Infection and effect of helminths are influenced and perhaps determined by micro-organisms. Mechanisms behind parasite-microbiome interactions are poorly understood, despite implications on host health. These interactions are typically studied for single helminth species in laboratory animal models, overlooking helminth diversity. Reviewing research on relationships between helminth and microbial diversity yielded 27 publications; most focused on human or other mammalian hosts, relying on natural exposure rather than experimental helminth inoculation. Only about half investigated host health outcomes. Remaining knowledge gaps warrant considering additional candidate model systems. Given the high helminthiasis burden and species diversity of helminths, we propose seeking models in the Global South, where a considerable proportion of research on diversity aspects of helminth-microbiome interactions took place. Low availability of genomic resources for helminths in the Global South, however, necessitates more integrative helminthological research efforts. Given substantial similarities in immune systems, several fishes are models for human health/disease. More effort could be done to establish this for cichlids, whose representatives in the African Great Lakes provide a well-delineated, closed natural system relevant to human health in view of fish-borne zoonoses and other water-borne parasites. A good baseline exists for these cichlids' genomics, parasitology, and microbiology. We suggest exploring African Great Lake cichlids as model hosts for interactions between microbial diversity, helminth diversity, and host health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Vanhove, Koblmüller, Fernandes, Hahn, Plusquin and Kmentová.)

Introduction: Parasitic diseases pose a significant global public health challenge, affecting billions of people and causing substantial economic losses in livestock and poultry. In the fight against these infections, neutrophils play a crucial role, employing various strategies, including the release of neutrophil extracellular traps (NETs). Recent studies have made significant progress in understanding NETs triggered by protozoa and helminths. However, a comprehensive bibliometric analysis that compiles these findings and identifies research hotspots and trends in this field is still lacking., Methods: We utilized the Web of Science Core Collection and Scopus databases to retrieve original articles on NETs induced by protozoa and helminths. After screening, the data was transferred to the visualization tools VOSviewer, Biblioshiny, and CiteSpace for analysis., Results: Our study included 159 original articles published in 69 journals, involving 909 authors from 270 institutions across 41 countries. Germany and Brazil have made the most significant contributions to the research on NETs and parasites, accounting for 45 and 32 publications, and 1,495 and 1,342 citations, respectively. Carlos Hermosilla and Anja Taubert (Justus Liebig University Giessen, Germany), and Elvira Saraiva (Federal University of Rio de Janeiro, Brazil), are leaders in the field, both in terms of publication output and citations. Frontiers in Immunology has consistently and significantly impacted the field, and an article in the Proceedings of the National Academy of Sciences of the United States of America providing the first direct evidence of NETs release in response to a parasite is by far the most cited. Current research focuses on malaria, Toxoplasma gondii , Besnoitia besnoiti , nematodes, and the mechanisms of NETs production and their effects on parasites and host cells. Emerging trends include therapeutic targeting of NETs and comparative studies across different host and parasite species., Conclusion: This study offers a comprehensive overview and visual analysis of NETs and parasites, highlighting key areas for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Muñoz-Caro, Saraiva and Mariante.)

Helminth infections are a major public health problem as they can cause long-term chronic infections in their hosts for which there is no effective vaccine. During the long-term interaction between helminths and their hosts, helminth-derived extracellular vesicles (EVs) can participate in host immunomodulatory processes by secreting bioactive molecules (BMAs). Growing data suggests that microRNAs (miRNAs) in helminth EVs have a significant impact on the host's immune system. The let-7 family is highly conserved among helminth EVs and highly homologous in the host, and its function in host-parasite crosstalk may reflect active selection for compatibility with the host miRNA machinery. In-depth studies targeting this aspect may better elucidate the mechanism of parasite-host interactions. Hence, this review summarizes the current studies on the cross-species involvement of helminth EV-derived let-7 in host immune regulation and discusses the barriers to related research and potential applications of helminth EVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhong, Guan and Jin.)

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frech, Omata, Schmalzl, Wirtz, Taher, Schett, Zaiss and Sarter.)

Helminths contribute a larger global burden of disease than both malaria and tuberculosis. These eukaryotes have caused human infections since before our earliest recorded history (i.e.: earlier than 1200 B.C. for Schistosoma spp.). Despite the prevalence and importance of these infections, helminths are considered a neglected tropical disease for which there are no vaccines approved for human use. Similar to other parasites, helminths are complex organisms which employ a plethora of features such as: complex life cycles, chronic infections, and antigenic mimicry to name a few, making them difficult to target by conventional vaccine strategies. With novel vaccine strategies such as viral vectors and genetic elements, numerous constructs are being defined for a wide range of helminth parasites; however, it has yet to be discussed which of these approaches may be the most effective. With human trials being conducted, and a pipeline of potential anti-helminthic antigens, greater understanding of helminth vaccine-induced immunity is necessary for the development of potent vaccine platforms and their optimal design. This review outlines the conventional and the most promising approaches in clinical and preclinical helminth vaccinology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Perera and Ndao.)

Competing Interests: PG is a co-founder of Paragen Bio, a biotech company that aims to translate and commercialise hookworm-derived proteins for inflammatory diseases. This has previously involved investment from pharma (Abbvie Inc) and venture capitalist firms (OneVentures, Brandon Capital). MS is founder and president of the biotech company NemaGen Discoveries. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Exposure to different organisms (bacteria, mold, virus, protozoan, helminths, among others) can induce epigenetic changes affecting the modulation of immune responses and consequently increasing the susceptibility to inflammatory diseases. Epigenomic regulatory features are highly affected during embryonic development and are responsible for the expression or repression of different genes associated with cell development and targeting/conducting immune responses. The well-known, "window of opportunity" that includes maternal and post-natal environmental exposures, which include maternal infections, microbiota, diet, drugs, and pollutant exposures are of fundamental importance to immune modulation and these events are almost always accompanied by epigenetic changes. Recently, it has been shown that these alterations could be involved in both risk and protection of allergic diseases through mechanisms, such as DNA methylation and histone modifications, which can enhance Th2 responses and maintain memory Th2 cells or decrease Treg cells differentiation. In addition, epigenetic changes may differ according to the microbial agent involved and may even influence different asthma or allergy phenotypes. In this review, we discuss how exposure to different organisms, including bacteria, viruses, and helminths can lead to epigenetic modulations and how this correlates with allergic diseases considering different genetic backgrounds of several ancestral populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fiuza, Fonseca, Meirelles, Marques, da Silva and Figueiredo.)

Helminths remain one of the most prolific pathogens in the world. Following infection helminths interact with various epithelial cell surfaces, including skin, lung, and gut. Recent works have shown that epithelial cells produce a series of cytokines such as TSLP, IL-33, and IL-25 that lead to the induction of innate and acquired type 2 immune responses, which we named Type 2 epithelial cytokines. Although basophils and eosinophils are relatively rare granulocytes under normal conditions (0.5% and 5% in peripheral blood, respectively), both are found with increased frequency in type 2 immunity, including allergy and helminth infections. Recent reports showed that basophils and eosinophils not only express effector functions in type 2 immune reactions, but also manipulate the response toward helminths. Furthermore, basophils and eosinophils play non-redundant roles in distinct responses against various nematodes, providing the potential to intervene at different stages of nematode infection. These findings would be helpful to establish vaccination or therapeutic drugs against nematode infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Obata-Ninomiya, Domeier and Ziegler.)

Helminths, including nematodes, cestodes and trematodes, are complex parasitic organisms that infect at least one billion people globally living in extreme poverty. Helminthic infections are associated with severe morbidity particularly in young children who often harbor the highest burden of disease. While each helminth species completes a distinct life cycle within the host, several helminths incite significant lung disease. This impact on the lungs occurs either directly from larval migration and host immune activation or indirectly from a systemic inflammatory immune response. The impact of helminths on the pulmonary immune response involves a sophisticated orchestration and activation of the host innate and adaptive immune cells. The consequences of activating pulmonary host immune responses are variable with several helminthic infections leading to severe, pulmonary compromise while others providing immune tolerance and protection against the development of pulmonary diseases. Further delineation of the convoluted interface between helminth infection and the pulmonary host immune responses is critical to the development of novel therapeutics that are critically needed to prevent the significant global morbidity caused by these parasites., (Copyright © 2020 Weatherhead, Gazzinelli-Guimaraes, Knight, Fujiwara, Hotez, Bottazzi and Corry.)

Background: The unique immunomodulatory capacity of helminth parasites has been investigated as a novel strategy in the prevention of allograft rejection after transplantation. This review was conducted to fully evaluate the specific effects of helminth therapy on allograft survival reported in published studies of animal models of allogeneic transplantation. Method: Following PRISMA protocol guidelines, a literature search was conducted using PubMed, MEDLINE via OvidSP, along with additional manual searches of selected reference lists. Publications describing helminth intervention within allograft transplantation models were screened for relevance to eligibility criteria. Primary and secondary outcomes were extracted using standardized data collection tables. The SYRCLE risk of bias assessment tool was used for quality assessment. Due to heterogeneity of study designs, meta-analysis could not be performed; rather outcomes are presented as a narrative synthesis with concept mapping. This review was registered in PROSPERO with ID: CRD42018097175. Results: The literature search generated 1,443 publications, which after screening for relevance to the eligibility criteria yielded 15 publications for qualitative analysis. All 15 publications reported improvement to allograft survival as a result of helminth therapy. This prolonged allograft survival was not significantly different when helminth-derived products were used compared to live infection. However, the extent of positive impact on allograft survival was noted to be dependent on study design factors, such as the chronicity of the live helminth infection, allograft type and the species/genus of helminth selected. Conclusion: Both live and product-based helminth therapy have potential applications as novel immune regulators or adjuncts for the prevention of allograft rejection. However, there were differences in efficacy between different worms and preparations of worm-derived products. Therefore, further studies are required to determine the most appropriate worm for a specific allograft, to elucidate the optimal dose and route of administration, and to better understand the modulation of immune responses that can mediate tolerance., (Copyright © 2020 Kiss, Burns, Donnelly and Hawthorne.)

Human intestinal helminth infection affects more than 1 billion people often in the world's most deprived communities. These parasites are one of the most prevalent neglected tropical diseases worldwide bringing huge morbidities to the host population. Effective treatments and vaccines for helminths are currently limited, and therefore, it is essential to understand the molecular sensors that the intestinal epithelium utilizes in detecting helminths and how the responding factors produced act as modulators of immunity. Defining the cellular and molecular mechanisms that enable helminth detection and expulsion will be critical in identifying potential therapeutic targets to alleviate disease. However, despite decades of research, we have only recently been able to identify the tuft cell as a key helminth sensor at the epithelial barrier. In this review, we will highlight the key intestinal epithelial chemosensory roles associated with the detection of intestinal helminths, summarizing the recent advances in tuft cell initiation of protective type 2 immunity. We will discuss other potential sensory roles of epithelial subsets and introduce enteroendocrine cells as potential key sensors of the microbial alterations that a helminth infection produces, which, given their direct communication to the nervous system via the recently described neuropod, have the potential to transfer the epithelial immune interface systemically., (Copyright © 2020 Faniyi, Wijanarko, Tollitt and Worthington.)

Soil-transmitted helminths represent a major global health burden with infections and infection-related comorbidities causing significant reductions in the quality of life for individuals living in endemic areas. Repeated infections and chronic colonization by these large extracellular worms in mammals led to the evolution of type-2 immunity characterized by the production of the type-2 cytokines interleukin (IL)-4, IL-5, and IL-13. Although a number of adaptive and innate immune cells produce type-2 cytokines, a key cellular source in the context of helminth infection is group 2 innate lymphoid cells (ILC2s). ILC2s promote mucosal barrier homeostasis, integrity, and repair by rapidly responding to epithelial cues in mucosal tissues. Though tissue-resident ILC2s (nILC2s) have been studied in detail over the last decade, considerably less is known with regard to a subset of inflammatory ILC2s (iILC2s) that migrate to the lungs of mice early after Nippostrongylus brasiliensis infection and are potent early producers of type-2 cytokines. This review will discuss the relationship and differences between nILC2s and iILC2s that establish their unique roles in anti-helminth immunity. We have placed particular emphasis on studies investigating iILC2 origin, function, and their potential long-term contribution to tissue-resident ILC2 reservoirs in settings of helminth infection., (Copyright © 2020 Miller and Reinhardt.)

Infection with soil-transmitted helminths (STH) remains a major burden on global health and agriculture. Our understanding of the immunological mechanisms that govern whether an individual is resistant or susceptible to infection is derived primarily from model infections in rodents. Typically, experimental infections employ an artificially high, single bolus of parasites that leads to rapid expulsion of the primary infection and robust immunity to subsequent challenges. However, immunity in natura is generated slowly, and is only partially effective, with individuals in endemic areas retaining low-level infections throughout their lives. Therefore, there is a gap between traditional model STH systems and observations in the field. Here, we review the immune response to traditional model STH infections in the laboratory. We compare these data to studies of natural infection in humans and rodents in endemic areas, highlighting crucial differences between experimental and natural infection. We then detail the literature to date on the use of "trickle" infections to experimentally model the kinetics of natural infection., (Copyright © 2020 Colombo and Grencis.)

Group 2 innate lymphoid cells (ILC2s) were first discovered in experimental studies of intestinal helminth infection-and much of our current knowledge of ILC2 activation and function is based on the use of these models. It is perhaps not surprising therefore that these cells have also been found to play a key role in mediating protection against these large multicellular parasites. ILC2s have been intensively studied over the last decade, and are known to respond quickly and robustly to the presence of helminths-both by increasing in number and producing type 2 cytokines. These mediators function to activate and repair epithelial barriers, to recruit other innate cells such as eosinophils, and to help activate T helper 2 cells. More recent investigations have focused on the mechanisms by which the host senses helminth parasites to activate ILC2s. Such studies have identified novel stromal cell types as being involved in this process-including intestinal tuft cells and enteric neurons, which respond to the presence of helminths and activate ILC2s by producing IL-25 and Neuromedin, respectively. In the current review, we will outline the latest insights into ILC2 activation and discuss the requirement for-or redundancy of-ILC2s in providing protective immunity against intestinal helminth parasites.

Type III IFNs are important players in immunity to viral and bacterial infections. However, their association with helminth infections has not been examined. To explore the association of Type III IFNs with Strongyloides stercoralis ( Ss ) infection, we examined the systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in Ss infected (INF, n = 44), helminth-uninfected (UN, n = 44) and in post-treatment INF individuals. We also examined the levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in whole blood culture supernatants stimulated with Ss somatic antigens, or PPD or LPS. Finally, we performed correlations of systemic Type III IFN levels with absolute numbers of dendritic cell subsets. Ss infection is characterized by elevated systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in comparison to UN individuals and a significant reduction following anthelmintic treatment. Ss infection is also characterized by elevated levels of unstimulated or Ss antigen stimulated levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, CXCL10/IP-10 and a significant reduction following treatment. In addition, Ss infection is characterized by increased numbers of plasmacytoid and myeloid dendritic cells in comparison to UN individuals, with a significant reduction following anthelmintic treatment of INF individuals. Finally, Ss infection exhibits a significant positive correlation between the systemic levels of IFN lambda-2 and IFN lambda-3 and the numbers of plasmacytoid dendritic cells. Thus, Ss infection is characterized by elevations in systemic and antigen-induced levels of Type III IFNs, which is positively associated with the numbers of plasmacytoid dendritic cells and reversed upon anthelmintic treatment.

Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.

Parasitic helminths are among the most pervasive pathogens of the animal kingdom. To complete their life cycle, these intestinal worms migrate through host tissues causing significant damage in their wake. As a result, infection can lead to malnutrition, anemia and increased susceptibility to co-infection. Despite repeated deworming treatment, individuals living in endemic regions remain highly susceptible to re-infection by helminths, but rarely succumb to excessive tissue damage. The chronicity of infection and inability to resist numerous species of parasitic helminths that have co-evolved with their hosts over millenia suggests that mammals have developed mechanisms to tolerate this infectious disease. Distinct from resistance where the goal is to destroy and eliminate the pathogen, disease tolerance is an active process whereby immune and structural cells restrict tissue damage to maintain host fitness without directly affecting pathogen burden. Although disease tolerance is evolutionary conserved and has been well-described in plant systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular networks that support disease tolerance during enteric stages of parasitic helminth infection and why this alternative host defense strategy may have evolved to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine.

Gastrointestinal nematodes are among the most prevalent parasites infecting humans and livestock worldwide. Infective larvae of the soil-transmitted nematode Ascaris spp. enter the host and start tissue migration by crossing the intestinal epithelial barrier. The initial interaction of the intestinal epithelium with the parasite, however, has received little attention. In a time-resolved interaction model of porcine intestinal epithelial cells (IPEC-J2) and infective Ascaris suum larvae, we addressed the early transcriptional changes occurring simultaneously in both organisms using dual-species RNA-Seq. Functional analysis of the host response revealed an overall induction of metabolic activity, without induction of immune responsive genes or immune signaling pathways and showing suppression of chemotactic genes like CXCL8/IL-8 or CHI3L1. Ascaris larvae, when getting in contact with the epithelium, showed induction of genes that orchestrate motor activity and larval development, such as myosin, troponin, myoglobin, and protein disulfide isomerase 2 (PDI-2). In addition, excretory-secretory products that likely facilitate parasite invasion were increased, among them, aspartic protease 6 or hyaluronidase. Integration of host and pathogen data in an interspecies gene co-expression network indicated links between nematode fatty acid biosynthesis and host ribosome assembly/protein synthesis. In summary, our study provides new molecular insights into the early factors of parasite invasion, while at the same time revealing host immunological unresponsiveness. Reproducible software for dual RNA-Seq analysis of non-model organisms is available at https://gitlab.com/mkuhring/project_asuum and can be applied to similar studies.

Helminth infections, by nematodes, trematodes, or cestodes, can lead to the modulation of host immune responses. This allows long-duration parasite infections and also impacts responses to co-infections. Surface, secreted, excreted, and shed proteins are thought to play a major role in modulation. A commonly reported feature of such immune modulation is the role of T regulatory (Treg) cells and IL-10. Efforts to identify helminth proteins, which cause immunomodulation, have identified candidates but not provided clarity as to a uniform mechanism driving modulation. In this study, we applied a bioinformatics systems approach, allowing us to analyze predicted T-cell epitopes of 17 helminth species and the responses to their surface proteins. In addition to major histocompatibility complex (MHC) binding, we analyzed amino acid motifs that would be recognized by T-cell receptors [T-cell-exposed motifs (TCEMs)]. All the helminth species examined have, within their surface proteins, peptides, which combine very common TCEMs with predicted high affinity binding to many human MHC alleles. This combination of features would result in large cognate T cell and a high probability of eliciting Treg responses. The TCEMs, which determine recognition by responding T-cell clones, are shared to a high degree between helminth species and with Plasmodium falciparum and Mycobacterium tuberculosis , both common co-infecting organisms. The implication of our observations is not only that Treg cells play a significant role in helminth-induced immune modulation but also that the epitope specificities of Treg responses are shared across species and genera of helminth. Hence, the immune response to a given helminth cannot be considered in isolation but rather forms part of an epitope ecosystem, or microenvironment, in which potentially immunosuppressive peptides in the helminth network via their common T-cell receptor recognition signals with T-cell epitopes in self proteins, microbiome, other helminths, and taxonomically unrelated pathogens. Such a systems approach provides a high-level view of the antigen-immune system signaling dynamics that may bias a host's immune response to helminth infections toward immune modulation. It may indicate how helminths have evolved to select for peptides that favor long-term parasite host coexistence.

Parasitic helminths are extremely resilient in their ability to maintain chronic infection burdens despite (or maybe because of) their hosts' immune response. Explaining how parasites maintain these lifelong infections, identifying the protective immune mechanisms that regulate helminth infection burdens, and designing prophylactics and therapeutics that combat helminth infection, while preserving host health requires a far better understanding of how the immune system functions in natural habitats than we have at present. It is, therefore, necessary to complement mechanistic laboratory-based studies with studies on wild populations and their natural parasite communities. Unfortunately, the relative paucity of immunological tools for non-model species has held these types of studies back. Thankfully, recent progress in high-throughput 'omics platforms provide powerful and increasingly practical means for immunologists to move beyond traditional lab-based model organisms. Yet, assigning both metabolic and immune function to genes, transcripts, and proteins in novel species and assessing how they interact with other physiological and environmental factors requires identifying quantitative relationships between their expression and infection. Here, we used supervised machine learning to identify gene networks robustly associated with burdens of the gastrointestinal nematode Heligmosomoides polygyrus in its natural host, the wild wood mice Apodemus sylvaticus . Across 34 mice spanning two wild populations and across two different seasons, we found 17,639 transcripts that clustered in 131 weighted gene networks. These clusters robustly predicted H. polygyrus burden and included well-known effector and regulatory immune genes, but also revealed a number of genes associated with the maintenance of tissue homeostasis and hematopoiesis that have so far received little attention. We then tested the effect of experimentally reducing helminth burdens through drug treatment on those putatively protective immune factors. Despite the near elimination of H. polygyrus worms, the treatment had surprisingly little effect on gene expression. Taken together, these results suggest that hosts balance tissue homeostasis and protective immunity, resulting in relatively stable immune and, consequently, parasitological profiles. In the future, applying our approach to larger numbers of samples from additional populations will help further increase our ability to detect the immune pathways that determine chronic gastrointestinal helminth burdens in the wild.