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Trichuris species are a globally important and prevalent group of intestinal helminth parasites, in which Trichuris muris (mouse whipworm) is an ideal model for this disease. This paper describes the first ever highly controlled and comprehensive investigation into the effects of T. muris infection on the faecal microbiota of mice and the effects on the microbiota following successful clearance of the infection. Communities were profiled using DGGE, 454 pyrosequencing, and metabolomics. Changes in microbial composition occurred between 14 and 28 days post infection, resulting in significant changes in α and β- diversity. This impact was dominated by a reduction in the diversity and abundance of Bacteroidetes, specifically Prevotella and Parabacteroides. Metabolomic analysis of stool samples of infected mice at day 41 showed significant differences to uninfected controls with a significant increase in the levels of a number of essential amino acids and a reduction in breakdown of dietary plant derived carbohydrates. The significant reduction in weight gain by infected mice probably reflects these metabolic changes and the incomplete digestion of dietary polysaccharides. Following clearance of infection the intestinal microbiota underwent additional changes gradually transitioning by day 91 towards a microbiota of an uninfected animal. These data indicate that the changes in microbiota as a consequence of infection were transitory requiring the presence of the pathogen for maintenance. Interestingly this was not observed for all of the key immune cell populations associated with chronic T. muris infection. This reflects the highly regulated chronic response and potential lasting immunological consequences of dysbiosis in the microbiota. Thus infection of T. muris causes a significant and substantial impact on intestinal microbiota and digestive function of mice with affects in long term immune regulation.

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes.

The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10R[alpha], IL-10R[beta], IL-22R[alpha] and IL-28R[alpha], modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22R[alpha] and IL-28R[alpha] are dispensable in the host response to whipworms, IL-10 signalling through IL-10R[alpha] and IL-10R[beta] is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10R[alpha] and IL-10R[beta] results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10R[alpha] and IL-10R[beta]-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10R[alpha] and IL-10R[beta] in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10R[alpha] on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10R[alpha] signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.

The intestinal nematode Trichuris trichiura is among the most common causes of human infectious disease worldwide. As for other soil-transmitted nematodes, its reproductive success and thus prevalence and intensity of infection in a given area strongly depend on environmental conditions. Characterization of the influence of environmental factors can therefore aid to identify infection hot spots for targeted mass treatment. We analyzed data from a cross-sectional survey including 6234 participants from nine distinct study sites in Mbeya region, Tanzania. A geographic information system was used to combine remotely sensed and individual data, which were analyzed using uni- and multivariable Poisson regression. Household clustering was accounted for and when necessary, fractional polynomials were used to capture non-linear relationships between T. trichiura infection prevalence and environmental variables. T. trichiura infection was restricted to the Kyela site, close to Lake Nyasa with only very few cases in the other eight sites. The prevalence of T. trichiura infection in Kyela was 26.6% (95% confidence interval (CI) 23.9 to 29.6%). Multivariable models revealed a positive association of infection with denser vegetation (prevalence ratio (PR) per 0.1 EVI units = 2.12, CI 1.28 to 3.50) and inverse associations with rainfall (PR per 100 mm = 0.54, CI 0.44 to 0.67) and elevation (PR per meter = 0.89, CI 0.86 to 0.93) while adjusting for age and previous worm treatment. Slope of the terrain was modelled non-linearly and also showed a positive association with T. trichiura infection (p-value p<0.001). Higher prevalences of T. trichiura infection were only found in Kyela, a study site characterized by denser vegetation, high rainfall, low elevation and flat terrain. But even within this site, we found significant influences of vegetation density, rainfall, elevation and slope on T. trichiura infection. The inverse association of rainfall with infection in Kyela is likely due to the fact, that rainfall in this site is beyond the optimum conditions for egg development. Our findings demonstrate that use of remotely sensed environmental data can aid to predict high-risk areas for targeted helminth control.

Human whipworm (Trichuris trichiura) infects approximately 1 in 15 people worldwide, representing the leading infectious cause of colitis and subsequent, inflammatory bowel disease (IBD). Current control measures focused on mass deworming have had limited success due to low drug efficacies. Vaccination would be an ideal, cost-effective strategy to induce protective immunity, leading to control of infection and transmission. Here we report the identification of whey acidic protein, a whipworm secretory protein, as a strong immunogen for inducing protective efficacy in a surrogate mouse T. muris infection model. The recombinant WAP protein (rTm-WAP49), as well as a single, highly conserved repeat within WAP (fragment 8) expressed as an Na-GST-1 fusion protein (rTm-WAP-F8+Na-GST-1), generate a strong T helper type 2 (Th2) immune response when delivered as subcutaneous vaccines formulated with Montanide ISA 720. Oral challenge with T. muris infective eggs following vaccination led to a significant reduction in worm burden of 48% by rTm-WAP49 and 33% by rTm-WAP-F8+Na-GST-1. The cellular immune correlates of protection included significant antigen-specific production of Th2 cytokines IL-4, IL-9, and IL-13 by cells isolated from the vaccine-draining inguinal lymph nodes, parasite-draining mesenteric lymph nodes, and spleen in mice vaccinated with either rTm-WAP49 or rTm-WAP-F8+Na-GST-1. The humoral immune correlates included a high antigen-specific ratio of IgG1 to IgG2a, without eliciting an IgE-mediated allergic response. Immunofluorescent staining of adult T. muris with WAP antisera identified the worm's pathogenic stichosome organ as the site of secretion of native Tm-WAP protein into the colonic mucosa. Given the high sequence conservation for the WAP proteins from T. muris and T. trichiura, the results presented here support the WAP protein to be further evaluated as a potential human whipworm vaccine candidate.

Although there has been extensive debate about whether Trichuris suis and Trichuris trichiura are separate species, only one species of the whipworm T. trichiura has been considered to infect humans and non-human primates. In order to investigate potential cross infection of Trichuris sp. between baboons and humans in the Cape Peninsula, South Africa, we sequenced the ITS1-5.8S-ITS2 region of adult Trichuris sp. worms isolated from five baboons from three different troops, namely the Cape Peninsula troop, Groot Olifantsbos troop and Da Gama Park troop. This region was also sequenced from T. trichiura isolated from a human patient from central Africa (Cameroon) for comparison. By combining this dataset with Genbank records for Trichuris isolated from other humans, non-human primates and pigs from several different countries in Europe, Asia, and Africa, we confirmed the identification of two distinct Trichuris genotypes that infect primates. Trichuris sp. isolated from the Peninsula baboons fell into two distinct clades that were found to also infect human patients from Cameroon, Uganda and Jamaica (named the CP-GOB clade) and China, Thailand, the Czech Republic, and Uganda (named the DG clade), respectively. The divergence of these Trichuris clades is ancient and precedes the diversification of T. suis which clustered closely to the CP-GOB clade. The identification of two distinct Trichuris genotypes infecting both humans and non-human primates is important for the ongoing treatment of Trichuris which is estimated to infect 600 million people worldwide. Currently baboons in the Cape Peninsula, which visit urban areas, provide a constant risk of infection to local communities. A reduction in spatial overlap between humans and baboons is thus an important measure to reduce both cross-transmission and zoonoses of helminthes in Southern Africa.

Background Soil-transmitted helminth (STH) infections are highly prevalent in the Philippines. Mapping the prevalence and high-intensity of STH co-infections can help guide targeted intervention programmes to reduce morbidity, especially among vulnerable school-aged children. In this study, we aimed to predict the spatial distribution of the prevalence of Ascaris lumbricoides and Trichuris trichiura co-infection and infection intensity classes in the Philippines to identify populations most in need of interventions. Methods Data on STH infections from 29,919 individuals during the nationwide parasitological survey in 2005 to 2007 were included in the analysis. To geographically predict the prevalence of A. lumbricoides and T. trichiura co-infections and infection intensity classes, Bayesian multinomial geostatistical models were built including age, sex, environmental variables and a geostatistical random effect. The number of individuals co-infected and belonging to each of the infection intensity classes in 2017 was forecast by combining our predictive prevalence maps with population density maps. Results Our models showed that school-aged children (5–19 years) are most at risk of A. lumbricoides and T. trichiura co-infections and of moderate/high infection intensity compared to other age groups. We identified target provinces where the likelihood of STH-associated morbidity was highest: Luzon (Bulacan, Benguet, Cavite, Sorsogon, Metropolitan Manila, Pampanga and Rizal), the Visayas (Cebu, Iloilo, Leyte and Negros Occidental), and in Mindanao (Agusan Del Norte, Davao Del Sur, Davao Oriental, Lanao Del Sur, Maguindanao, Misamis Oriental, Sulu and Zamboanga Del Sur). Luzon had the highest estimated number of school-aged children with A. lumbricoides and T. trichiura co-infections (estimated total 89,400), followed by the Visayas (38,300) and Mindanao (20,200). Conclusions Our study provided epidemiological evidence to highlight national priority areas for controlling co-infections and high intensity infections in the Philippines. Our maps could assist more geographically targeted interventions to reduce the risk of STH-associated morbidity in the Philippines.

The identification of parasites in ancient human remains can address questions of past health, disease, mobility and mortuary customs. Archaeoparasitological evidence from Russia is, however, almost absent. This study presents the first such evidence in the form of a helminth infection in a mummified individual from the southern Siberian site of Doge-Bary II, the burial ground of a nomadic Iron Age community. Despite the removal of the intestines as part of the mummification procedure, the residual eggs of Trichuris trichiura , a non-indigenous species of whipworm, were detected. This evidence provides the first confirmation of prehistoric contact between southern Siberian nomads and distant agricultural areas, such as China and Central Asia.

Albendazole/ivermectin combination therapy is a promising alternative to benzimidazole monotherapy alone for Trichuris trichiura control. We used fecal DNA metabarcoding to genetically characterize Trichuris spp. populations in patient samples from Côte d'Ivoire showing lower (egg reduction rate <70%) albendazole/ivermectin sensitivity than those from Laos and Tanzania (egg reduction rates >98%). Internal transcribed spacer (ITS) 1 and ITS2 metabarcoding revealed the entire detected Côte d'Ivoire Trichuris population was phylogenetically distinct from T. trichiura found in Laos and Tanzania and was more closely related to T. suis. Mitochondrial genome sequencing of 8 adult Trichuris worms from Côte d'Ivoire confirmed their species-level differentiation. Sequences from human patients in Cameroon and Uganda and 3 captive nonhuman primates suggest this novel species, T. incognita, is distributed beyond Côte d'Ivoire and has zoonotic potential. Continued surveillance by using fecal DNA metabarcoding will be needed to determine Trichuris spp. geographic distribution and control strategies.

Trichuris whipworms cause disease and morbidity in humans and other animals. Their prolonged intestinal infections persist despite intact immune systems of their hosts and are attributed to immunomodulatory activities of their secretions. The p43 (Tm-DLP-1) protein of Trichuris muris of mice comprises 95% of the protein secreted by adult parasites, binds matrix proteoglycans, and has immune cytokine (IL-13)-neutralising activity. Using fluorescence-based methods we show that p43 binds fatty acids and retinol, including signalling lipids or precursors thereof. The orthologue of p43 from the human whipworm, Trichuris trichiura, exhibits similar lipid-binding activity. From the known molecular structure of p43, we explore the existence of extensive surface-accessible cavities with diverse surface charge characteristics which may indicate binding of diverse small molecule types, and its internally duplicated subdomains likely possess divergent characteristics. p43 represents a novel protein type (“dorylipophorin”) only known in Dorylaimia (Clade I) nematodes. We demonstrate that p43 is the dominant protein in Trichuris’s pseudocoelomic fluid, replacing the major internal lipid transporters of all other nematode clades, representing an ancient functional dichotomy. In Trichuris , and potentially other Clade I parasites of plants and animals, these proteins’ lipid-binding activities may be adapted for both internal physiological and external immunomodulatory activities.