Neuroschistosomiasis: A Case Report and Review of Literature.

Spinal cord involvement is a rare complication of the schistosomiasis manifesting as myeloradiculopathy, medullary or conus-cauda equina syndrome which can lead to potentially serious long-term disability. Computed tomography and magnetic resonance imaging coupled with biochemical parameters have become the mainstay of diagnosis. Biopsy which is the gold standard of diagnosis demonstrating the organism is usually reserved for cases of diagnostic challenge. We report a rare case of upper thoracic spinal cord schistosomiasis diagnosed by biopsy in an 18-year-old male migrant presenting to a spine and orthopaedic centre in Ghana with complaints of upper back pain and associated myeloradiculopathy symptoms. Initial suspicion of intramedullary cord tumour was made based on magnetic resonance imaging findings warranting biopsy which revealed schistosoma spp. He was treated with anthelminthics and corticosteroids with a resolution of symptoms.

Anthelminthic Veterinary Medicines Interactions with the Soil Microbiota.

Anthelminthics (AHs) are used to control gastrointestinal nematodes (GINs) in productive animals. They are rapidly excreted by animals, ending up in soil through direct deposition of animal dung or application of animal excreta as manures. Most environmental research on AHs has focused on their toxicity to aquatic organisms and soil fauna while their interactions with the soil microbiota, a key component of a functioning soil ecosystem, have been overlooked. In this article, we summarize current knowledge on the interactions of Ahs with the soil (micro) biota, we highlight recent evidence for the toxicity of AHs on soil microorganisms and discuss those results in the frame of the current environmental risk assessment (ERA) of veterinary medicines.

Isolation of soil bacteria able to degrade the anthelminthic compound albendazole.

Anthelmintic (AHs) veterinary drugs constitute major environmental contaminants. The use of AH-contaminated fecal material as manures in agricultural settings constitutes their main route of environmental dispersal. Once in soils, these compounds induce toxic effects to soil fauna and soil microbiota, both having a pivotal role in soil ecosystem functioning. Therefore, it is necessary to identify mitigation strategies to restrict the environmental dispersal of AHs. Bioaugmentation of AH-contaminated manures or soils with specialized microbial inocula constitutes a promising remediation strategy. In the present study, we aimed to isolate microorganisms able to actively transform the most widely used benzimidazole anthelminthic albendazole (ABZ). Enrichment cultures in minimal growth media inoculated with a soil known to exhibit rapid degradation of ABZ led to the isolation of two bacterial cultures able to actively degrade ABZ. Two oxidative products of ABZ, ABZSO and ABZSO2, were detected at low amounts along its degradation. This suggested that the oxidation of ABZ is not a major transformation process in the isolated bacteria which most probably use other biotic pathways to degrade ABZ leading to the formation of products not monitored in this study. Full length sequencing of their 16S rRNA gene and phylogenetic analysis assigned both strains to the genus Acinetobacter. The sequences were submitted in GeneBank NCBI, database with the accession numbers OP604271 to OP604273. Further studies will employ omic tools to identify the full transformation pathway and the associated genetic network of Acinetobacter isolates, information that will unlock the potential use of these isolates in the bioaugmentation of contaminated manures.

Trichuris muris egg-hatching assay for anthelminthic drug discovery and characterization.

Trichuriasis is a neglected tropical disease widely distributed among tropical and sub-tropical areas and associated with poverty and lack of access to safe drinking water, sanitation and hygiene. Existing drugs have limited efficacy and face a constant risk of developing resistance, necessitating the search for alternative treatments. However, drug discovery efforts are sparse and little research has been performed on anthelminthic effects on embryonated eggs, the infectious life stage of Trichuris spp. We examined bacterial species dependent egg hatching of the murine model parasite Trichuris muris and identified Escherichia coli, Pseudomonas aeruginosa and Enterobacter hormaechei effective as hatching inducers, resulting in hatching yields of 50-70%. Streptococcus salivarius, reported to be associated with reduced drug efficacy of ivermectin-albendazole coadministration in Trichuris trichiura infected patients, did not promote egg hatching in vitro. We optimized hatching conditions using E. coli grown in luria broth or brain-heart infusion media to reach consistently high hatching yields to provide a sensitive, robust and simple egg-hatching assay. Oxantel pamoate demonstrated the strongest potency in preventing hatching, with an EC50 value of 2-4 µM after 24 h, while pyrantel pamoate, levamisole and tribendimidine exhibited only moderate to weak inhibitory effects. Conversely, all tested benzimidazoles and macrolide anthelminthics as well as emodepside failed to prevent hatching (EC50 > 100 µM). Our study demonstrates that egg-hatching assays complement larval and adult stage drug sensitivity assays, to expand knowledge about effects of current anthelminthics on Trichuris spp. Further, the developed T. muris egg-hatching assay provides a simple and cheap screening tool that could potentially lead to the discovery of novel anthelminthic compounds.

Interactions of anthelmintic veterinary drugs with the soil microbiota: Toxicity or enhanced biodegradation?

Anthelmintic (AH) compounds are used to control gastrointestinal nematodes (GINs) in livestock production. They are only partially metabolized in animals ending in animal excreta whose use as manures leads to AH dispersal in agricultural soils. Once in soil, AHs interact with soil microorganisms, with the outcome being either detrimental, or beneficial. We aimed to disentangle the mechanisms of these complex interactions. Two soils previously identified as « fast ¼ or « slow¼, regarding the degradation of albendazole (ABZ), ivermectin (IVM), and eprinomectin (EPM), were subjected to repeated applications at two dose rates (1, 2 mg kg-1and 10, 20 mg kg-1). We hypothesized that this application scheme will lead to enhanced biodegradation in «fast ¼ soils and accumulation and toxicity in «slow ¼ soils. Repeated application of ABZ resulted in different transformation pathways in the two soils and a clear acceleration of its degradation in the «fast ¼ soil only. In contrast residues of IVM and EPM accumulated in both soils. ABZ was the sole AH that induced a consistent reduction in the abundance of total fungi and crenarchaea. In addition, inhibition of nitrification and reduction in the abundance of ammonia-oxidizing bacteria (AOB) and archaea (AOA) by all AHs was observed, while commamox bacteria were less responsive. Amplicon sequencing analysis showed dose-depended shifts in the diversity of bacteria, fungi, and protists in response to AHs application. ABZ presented the most consistent effect on the abundance and diversity of most microbial groups. Our findings provide first evidence for the unexpected toxicity of AHs on key soil microbial groups that might have to be considered in a regulatory context.

Development of a hookworm egg hatching assay to determine the ovicidal effects of anthelminthics.

BACKGROUND: Few anthelminthics are currently available, manifesting the urgent need for new treatment options. In vitro profiling of current anthelminthics against larval and adult stage helminths displayed varying effects on closely related worm species and between life stages of the same species. Conversely, limited research has been performed on the egg stage of human hookworms, and the effects of investigational compounds on the egg stage are not routinely assessed. METHODS: We profiled the development and hatching of Heligmosomoides polygyrus, Ancylostoma duodenale and Necator americanus eggs isolated from rodent faeces in liquid media with various nutrient levels, osmolar concentrations, and acidities in dependence on incubation temperature and light exposure. Incubation conditions were optimised to allow the study of drug effect on immature and embryonated eggs. We analysed concentration-effect relationships of commercially available anthelminthics over 72 h. RESULTS: Rapid embryonation and hatching were observed at room temperature with and without light exposure without nutrient supplementation in a wide range of acidities. Hookworms hatched optimally at room temperature in PBS achieving > 75% hatching over 34 h. Developmental delays were seen when eggs were stored at 4 °C with no effect on viability. Similar delays were also seen with increased osmolar concentrations resulting in decreased viability. Benzimidazole anthelminthics effectively reduced the viability and prevented hatching of hookworm eggs, with albendazole and thiabendazole eliciting particularly potent effects at EC50 values below 1 µM. Macrolide anthelminthics as well as emodepside, oxantel pamoate, and pyrantel pamoate were inactive while monepantel, levamisole, and tribendimidine displayed varied potencies among the hookworm species. CONCLUSION: The presented egg-hatching assay will complement ongoing anthelminthic drug discovery and allow a full characterisation of drug activity against all life stages. In the development and application of the egg-hatching assay, good accordance was observed between the three hookworm species evaluated. Marketed anthelminthics show differences of drug action compared to larval and adult stages highlighting the importance of profiling drug activity against all life stages.

Repurposing Anthelmintics: Rafoxanide- and Copper-Functionalized SBA-15 Carriers against Methicillin-Resistant Staphylococcus aureus.

The development of materials that can more efficiently administer antimicrobial agents in a controlled manner is urgently needed due to the rise in microbial resistance to traditional antibiotics. While new classes of antibiotics are developed and put into widespread usage, existing, inexpensive compounds can be repurposed to fight bacterial infections. Here, we present the synthesis of amine-functionalized SBA-15 mesoporous silica nanomaterials with physisorbed rafoxanide (RFX), a commonly used salicylanilide anthelmintic, and anchored Cu(II) ions that exhibit enhanced antimicrobial efficacy against the pathogenic bacterium Staphylococcus aureus. The synthesized nanomaterials are structurally characterized by a combination of physicochemical, thermal, and optical methods. Additionally, release studies are carried out in vitro to determine the effects of pH and the synthetic sequence used to produce the materials on Cu(II) ion release. Our results indicate that SBA-15 mesoporous silica nanocarriers loaded with Cu(II) and RFX exhibit 10 times as much bactericidal action against wild-type S. aureus as the nanocarrier loaded with only RFX. Furthermore, the synthetic sequence used to produce the nanomaterials could significantly affect (enhance) their bactericidal efficacy.

In Vitro and In Vivo Antischistosomal Activity Profiling and Pharmacokinetics of Ozonide Carboxylic Acids.

Praziquantel, the only drug in clinical use for the treatment and control of schistosomiasis, is inactive against developing infections. Ozonides are synthetic peroxide derivatives inspired by the naturally occurring artemisinin and show particularly promising activity against juvenile schistosomes. We conducted an in-depth characterization of the in vitro and in vivo antischistosomal activity and pharmacokinetics of lead ozonide carboxylic acid OZ418 and four of its active analogs. In vitro, the ozonides featured rapid and consistent activity against schistosomula and adult schistosomes at double-digit micromolar EC50 values. Potency did not vary considerably between Schistosoma spp. The zwitterionic OZ740 and OZ772 were more active in vivo compared to their non-amphoteric carboxylic acids OZ418 and OZ748, despite their much lower systemic plasma exposure (AUC). The most active compound in vivo was ethyl ester OZ780, which was rapidly transformed to its parent zwitterion OZ740 and achieved ED50 values of 35 ± 2.4 and 29 ± 2.4 mg/kg against adult and juvenile Schistosoma mansoni, respectively. Ozonide carboxylic acids represent promising candidates for further optimization and development due to their good efficacy against both life stages together with their broad activity range against all relevant parasite species.

The Prevalence and Control of Lungworms of Pastoral Ruminants in Iran.

Lungworms of the genera Dictyocaulus, Muellerius, Protostrongylus, and Cystocaulus are common helminths of domestic and wild ruminants with substantial veterinary and economic importance. Several studies have assessed the presence and prevalence of lungworm infections in ruminants in Iran. This report compiles the available scientific information about the occurrence of lungworms in domestic and wild ruminants in Iran between 1931 and June 2022 to give an insight into their epidemiology, and where possible to describe drug treatment efficacy. For this purpose, national and international scientific databases were searched. Overall, 54 publications comprising 33 articles in peer-reviewed journals, 8 conference papers, and 13 dissertations were evaluated regarding prevalence data; and an additional 4 peer-reviewed articles were evaluated regarding drug efficacy. Seven species of lungworms, namely Dictyocaulus filaria, Dictyocaulus viviparus, Dictyocaulus eckerti, Protostrongylus rufescens, Protostrongylus raillietti, Muellerius capillaris, and Cystocaulus ocreatus have been recorded from different ruminant hosts in Iran. Thirty-three studies conducted on small ruminant (sheep and goat) lungworms reported prevalences of lungworm infection of 11.6%, 45.81% and 66.29% using abattoir meat inspection, Baermann technique and fecal flotation, respectively. Eight studies conducted on large ruminants (cattle and water buffalo) reported prevalences of infection of 14.83%, 13.98% and 5% using abattoir meat inspection, the Baermann technique and fecal flotation, respectively. The prevalence of infection in wild ruminants was variable across examined species; 38% in urial, 37% in wild goats, 5% in goitered gazelles and 67% in red deer, in addition to a single case report in roe deer. There are few contemporary studies assessing the efficacy of currently available broad-spectrum anthelmintic compounds against lungworms in Iran. The high prevalence of multiple lungworm species in Iran, combined with a lack of information about drug efficacy, supports the need to improve the understanding of these important nematode parasites and inform the development of sustainable control strategies. The aim of this review and meta-analysis is to provide a baseline for future conventional parasitology and next generation molecular epidemiological studies of lungworm infection in pastoral ruminants in Iran.

Improving translational power in antischistosomal drug discovery.

Schistosomiasis is a poverty-associated tropical disease caused by blood dwelling trematodes that threaten approximately 10% of the world population. Praziquantel, the sole drug currently available for treatment, is insufficient to eliminate the disease and the clinical drug development pipeline is empty. Here, we review the characteristics of the patent Schistosoma mansoni mouse model used for in vivo antischistosomal drug discovery, highlighting differences in the experimental set-up across research groups and their potential influence on experimental results. We explore the pharmacokinetic/pharmacodynamic relationship of selected drug candidates, showcasing opportunities to improve the drug profile to accelerate the transition from the early drug discovery phase to new clinical candidates.

Discovery of novel antischistosomal scaffolds from the open access Pandemic Response Box.

BACKGROUND: Treatment and control of schistosomiasis rely on a single drug, praziquantel. New orally active antischistosomals featuring novel molecular scaffolds are urgently needed to prevent the emergence of resistance. METHODS: We screened 400 drug-like compounds contained in the open-access Pandemic Response Box (PRB) against newly transformed schistosomula (NTS) at a concentration of 10 µM scoring death, changes in motility, and morphological alterations. Compounds displaying an activity ≥66% at 72 h underwent testing against adult Schistosoma mansoni in vitro. Fast-acting (≥66% at 24 h), nontoxic drugs focusing on late-stage and approved drugs were investigated in the patent S. mansoni mouse model. RESULTS: We identified 26 hits active against NTS, of which 17 elicited ≥66% activity against adult S. mansoni following 24 h of drug exposure. The highest activity against adult S. mansoni was observed with MMV1581558 (EC50 value of 0.18 ± 0.01 µM) and nitazoxanide (0.47 ± 0.07 µM). Of the five compounds tested in vivo, MMV1581558 and the approved drug ozanimod reduced average worm burden versus controls by 42 % and 36 %, respectively, after a single oral dose of 200 mg/kg bodyweight in mice harboring a chronic S. mansoni infection. CONCLUSION: MMV1581558 discovered from screening the PRB represents a novel antischistosomal scaffold with high in vitro antischistosomal activity amenable to chemical modification for drug development.

In Vitro Testing of Alternative Synthetic and Natural Antiparasitic Compounds against the Monogenean Sparicotyle chrysophrii.

Gill monogenean Sparicotyle chrysophrii is considered the most detrimental fish parasite to the Mediterranean aquaculture. Treatment of sparicotylosis relies on frequent gill inspections correlated with the seasonal increase in seawater temperature, application of functional feeds, and treatments with formalin baths where permitted. While the latter is bound to be banned in Europe, other synthetic anthelminthics, such as praziquantel and ivermectin, are prone to induce resistance in the parasites. Therefore, we investigated, in vitro, 14 synthetic and natural compounds against adult S. chrysophrii, developing dose-response modelsm and estimated toxicity levels at 20%, 50%, and 80% parasite mortality. Bactericidal activity of target compounds was also tested in two important aquaculture bacteria; Vibrio harveyi and V. anguillarum, while their potential host toxicity was evaluated in gilthead seabream SAF-1 cell line. Synthetic compound bithionate sodium exerted the most potent toxicity against the monogenean, no host cytotoxicity, and a medium and high potency against two bacterial pathogens. In comparison, target natural compounds were approximately 20 (cedrol) or up to 154 times (camphor) less toxic for the monogenean. Rather than completely dismissing natural compounds, we suggest that their application in combination with synthetic drugs, especially if administered in the feed, might be useful in sparicotylosis treatment.

Pediatric Pharmacotherapy: Anthelminthic Treatment.

Helminths, including nematodes, trematodes, and cestodes, are parasitic worms that infect approximately two billion people worldwide and cause significant morbidity particularly in children. Helminth-induced morbidity is associated with disease burden which typically is greatest in preschool and school-aged children. Preventive chemotherapy through mass drug administration programs has been instituted globally to reduce worm burden and morbidity in children through administration of anthelminthic therapy at regular intervals in helminth endemic areas. Despite these interventions, elimination of these infections remains elusive due to high rates of reinfection and concern for emerging anthelminthic resistance. Although children harbor the greatest burden of disease, minimal pharmacokinetic, safety, and tolerability data is available for young children, limiting their use. Novel anthelminthic therapies are critically needed to combat helminth disease with particular attention paid toward medications that can be used in young children to reduce global helminth-induced morbidity.

Toxicological, hematological and immunological effects of levamisole and ivermectin diet supplementation on Colossoma macropomum (Serrasalmidae).

This study investigated the toxicological, hematological and immunological effects of diets supplemented with levamisole and ivermectin on Colossoma macropomum. Fish were fed for 24, 96 and 240 h with diets containing 300, 600, 900 and 1200 mg of levamisole kg-1 of feed. None of the levamisole concentrations caused either mortality or behavioral alterations among the fish over 10 d of feeding. In comparison, a single feeding of ivermectin at 4500, 9000, 13500 or 18000 mg kg-1 caused 100% mortality among the fish within 10 h. There were no alterations in erythrocyte parameters or albumin in any treatments with levamisole after 24, 96 and 240 h of feeding. At concentrations of 900 and 1200 mg kg-1, levamisole caused decreases in the albumin-to-globulin ratio compared to the control group and the 300 and 600 mg kg-1 diet treatment groups. Levels of glucose and total plasma protein were higher in the fish fed with 600, 900 and 1200 mg kg-1 than in the controls and the 300 mg kg-1 diet treatment group. After 10 d of receiving feed supplemented with levamisole, globulin levels were higher in the 600 mg kg-1 group than in the controls. Respiratory burst activity of leukocytes also increased in the fish supplemented with the 900 and 1200 mg kg-1 diets compared to the controls and other treatments. This is the first study to investigate how diets supplemented with these drugs affect C. macropomum. Our research indicates that all the levamisole concentrations tested can be used in the diet of C. macropomum for antiparasitic treatments against helminth species, and that dietary treatments with levamisole can stimulate components of the innate immune system.

Early Antischistosomal Leads Identified from in Vitro and in Vivo Screening of the Medicines for Malaria Venture Pathogen Box.

As part of the control and elimination strategy of human schistosomiasis, preventive chemotherapy relies on a single drug, praziquantel. Facing an almost dry drug development pipeline, screening the Pathogen Box from the Medicines for Malaria Venture (MMV), provides a unique opportunity to possibly expand the pool of potent molecules against schistosomiasis. The activity of 400 compounds from this open-access library was first screened in vitro on the larval stage of Schistosoma mansoni. The hits were then tested on adult worms. Eleven leads were identified and tested for albumin-binding and activity on adult S. haematobium. In parallel, a rudimental structure-activity relationship analysis was performed on the 112 available analogues of three leads, yielding another 30 molecules active against both larval and adult stages of S. mansoni. Seven leads, selected on druglikeness, pharmacokinetic properties, and availability, plus auranofin were tested in mice harboring a chronic S. mansoni infection. MMV022029 and MMV022478 revealed the highest worm burden reductions of 67.8 and 70.7%, respectively. This study provided a series of new potent scaffolds and pharmacophores that could be used to design and develop suitable alternative(s) to praziquantel.

The impact of anthelmintic drugs on weight gain of smallholder goats in subtropical regions.

Helminth infections are recognised as a major impediment to the productivity of goats in smallholder production systems. We used a multilevel framework to estimate the impact that administration of locally available anthelminthic drugs can have on the weight gains of goats in smallholder settings in India and Tanzania. We recruited 234 goats from 92 households from Odisha state in India and 253 goats from 15 households from Dodoma region in Tanzania. The goats were non-pregnant adult females, and from each household a minimum of two goats were recruited wherever possible. Each goat was randomly assigned to treatment with a locally available anthelminthic drug, or non-treatment. Each animal was tagged, weighed and had its body condition score (BCS) assessed. Animals were followed up after 28 and 56 days and re-weighed. To account for the local variations in exposure to helminths and for variations between households and herds, the data were analysed in a multilevel mixed model with herd in village as nested random effects. Over the 56 days of study, the non-treated goats in India had gained a mean of 30.64 g per day (a daily gain of 0.23% baseline body weight) and in Tanzania 66.01 g per day (0.33% baseline body weight). From the mixed model, the treated goats in India gained a mean of 25.22 g per day more than non-treated goats, this is significantly greater than the weight gain in non-treated goats (p < 0.001). In Tanzania treated goats gained a mean of 9.878 g per day more than non-treated goats, which is also significantly greater than non-treated goats (p = 0.007). Furthermore, in India and Tanzania, goats with a lighter weight at the baseline survey gained greater amounts of weight. In both studies the BCS of the treated goats improved by a greater amount than the non-treated goats. In this study we have demonstrated that in certain settings, the administration of anthelminthic drugs has a clear beneficial impact on goat weight.

Off-target effects of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel-pamoate, and albendazole plus oxantel-pamoate on the human gut microbiota.

Soil-transmitted helminths infect 1.5 billion people worldwide. Treatment with anthelminthics is the key intervention but interactions between anthelminthic agents and the gut microbiota have not yet been studied. In this study, the effects of four anthelminthic drugs and combinations (tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel-pamoate, and albendazole plus oxantel-pamoate) on the gut microbiota were assessed. From each hookworm infected adolescent, one stool sample was collected prior to treatment, 24 h post-treatment and 3 weeks post-treatment, and a total of 144 stool samples were analyzed. The gut bacterial composition was analyzed using 16S rRNA gene sequencing. Tribendimidine given alone or together with oxantel-pamoate, and the combination of albendazole and oxantel pamoate were not associated with any major changes in the taxonomic composition of the gut microbiota in this population, at both the short-term post-treatment (24 h) and long-term post-treatment (3 weeks) periods. A high abundance of the bacterial phylum Bacteroidetes was observed following administration of tribendimidine plus ivermectin 24 h after treatment, due predominantly to difference in abundance of the families Prevotellaceae and Candidatus homeothermaceae. This effect is transient and disappears three weeks after treatment. Higher abundance of Bacteroidetes predicts an increase in metabolic pathways involved in the synthesis of B vitamins. This study highlights a strong relationship between tribendimidine and ivermectin administration and the gut microbiota and additional studies assessing the functional aspects as well as potential health-associated outcomes of these interactions are required.

Screening a repurposing library, the Medicines for Malaria Venture Stasis Box, against Schistosoma mansoni.

BACKGROUND: The development of new treatments against schistosomiasis is imperative but lacks commercial interest. Drug repurposing represents a suitable strategy to identify potential treatments, which have already unblocked several essential steps along the drug development path, hence reducing costs and timelines. Promoting this approach, the Medicines for Malaria Venture (MMV) recently distributed a drug repurposing library of 400 advanced lead candidates (Stasis Box). METHODS: All 400 compounds were initially tested in vitro against the larval stage of Schistosoma mansoni at 10 µM. Hits progressed to screening on adult worms and were further characterised for IC50, cytotoxicity and selectivity. Ten lead compounds were tested in mice harbouring a chronic S. mansoni infection. RESULTS: Eleven of the 37 compounds active on the larval stage were also highly active on adult worms in vitro (IC50 = 2.0-7.5 µM). IC50 values on adult S. mansoni decreased substantially in the presence of albumin (7.5-123.5 µM). Toxicity to L6 and MRC cells was moderate. A moderate worm burden reduction of 51.6% was observed for MMV690534, while the other 9 compounds showed low activity. None of the in vivo results were statistically significant (P > 0.05). CONCLUSIONS: Phenotypic screening of advanced lead compounds is a simple and resource-low method to identify novel anthelminthics. None of the promising hits of the Stasis Box identified in vitro against S. mansoni yielded acceptable worm burden reductions in vivo, which might be due to the high plasma protein binding. Since the in vitro hits interfere with different drug targets, they might provide a starting point for target based screening and structure-activity relationship studies.

The Immune and Non-Immune Pathways That Drive Chronic Gastrointestinal Helminth Burdens in the Wild.

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.