Most inbred strains of mouse infected with the intestinal nematode Trichuris muris are resistant to infection expelling the parasite before adult worms establish. However, a few susceptible strains exist that are incapable of worm expulsion and harbor chronic infections of mature adult worms. Analyses of in vitro cytokine production by cells from the draining lymph node (mesenteric lymph node) have indicated that expulsion phenotype is tightly correlated with the selective expansion of helper T cells (Th) of the Th1 or Th2 cell subset within the mesenteric lymph node, resulting in susceptibility and resistance to T. muris, respectively. We have now confirmed and extended our in vitro observations in a series of experiments involving the in vivo manipulation of host cytokine levels. Depletion of interferon (IFN)-gamma in normally susceptible mice resulted in expulsion of the parasite, representing the first evidence for a role for IFN-gamma in the establishment of chronic helminth infection. Blocking interleukin (IL)-4 function in normally resistant animals prevented the generation of a protective immune response allowing adult stages of the parasite to develop. Conversely the administration of IL-4 to a normally susceptible host facilitated expulsion and indeed enabled established adult worms to be expelled when administered late in infection. In all cases assessment of a variety of in vivo parameters indicative of a Th1- or Th2-type response (parasite-specific immunoglobulin (Ig) G2a and the parasite-specific IgG1, total IgE levels and intestinal mastocytosis, respectively) demonstrated that the in vivo modulation of a Th1- or Th2-specific cytokine allowed the reciprocal Th cell subset to expand and become dominant with dramatic consequences for worm expulsion.

https://rupress.org/jem/article-pdf/179/1/347/1395374/347.pdf

Cytokine-mediated regulation of chronic intestinal helminth infection.

IL-33 (IL-1F11) binds ST2 (IL-1R4), both of which are associated with optimal CD4+ Th2 polarization. Exogenous IL-33 drives induction of Th2-associated cytokines and associated pathological changes within the gut mucosa. Th2 polarization is also a prerequisite to expulsion of the intestinal-dwelling nematode Trichuris muris. In this study, we demonstrate that IL-33 mRNA is expressed early during parasite infection and susceptible mice can be induced to expel the parasite by a regime of exogenous IL-33 administration. IL-33 prevents an inappropriate parasite-specific Th1-polarized response and induces IL-4, IL-9, and IL-13. This redirection requires the presence of T cells and must occur at the initiation of the response to the pathogen. Interestingly, exogenous IL-33 also induced thymic stromal lymphopoietin mRNA within the infected caecum, an epithelial cell-restricted cytokine essential for the generation of Th2-driven parasite immunity. IL-33 also acts independently of T cells, altering intestinal pathology in chronically infected SCID mice, leading to an increased crypt length and intestinal epithelial cell proliferation, but reducing goblet cell hyperplasia. Thus, the ability of IL-33 to induce Th2 responses has functional relevance in the context of intestinal helminth infection, particularly during the initiation of the response.

IL-33, a Potent Inducer of Adaptive Immunity to Intestinal Nematodes

Intestinal epithelial cells (IECs) produce thymic stromal lymphopoietin (TSLP); however, the in vivo influence of TSLP-TSLP receptor (TSLPR) interactions on immunity and inflammation in the intestine remains unclear. We show that TSLP-TSLPR interactions are critical for immunity to the intestinal pathogen Trichuris. Monoclonal antibody-mediated neutralization of TSLP or deletion of the TSLPR in normally resistant mice resulted in defective expression of Th2 cytokines and persistent infection. Susceptibility was accompanied by elevated expression of interleukin (IL) 12/23p40, interferon (IFN) gamma, and IL-17A, and development of severe intestinal inflammation. Critically, neutralization of IFN-gamma in Trichuris-infected TSLPR(-/-) mice restored Th2 cytokine responses and resulted in worm expulsion, providing the first demonstration of TSLPR-independent pathways for Th2 cytokine production. Additionally, TSLPR(-/-) mice displayed elevated production of IL-12/23p40 and IFN-gamma, and developed heightened intestinal inflammation upon exposure to dextran sodium sulfate, demonstrating a previously unrecognized immunoregulatory role for TSLP in a mouse model of inflammatory bowel disease.

https://rupress.org/jem/article-pdf/206/3/655/1200058/jem_20081499.pdf

TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis

Increasing incidence of inflammatory bowel diseases, such as Crohn's disease, in developed nations is associated with changes to the microbial environment, such as decreased prevalence of helminth colonization and alterations to the gut microbiota. We find that helminth infection protects mice deficient in the Crohn's disease susceptibility gene Nod2 from intestinal abnormalities by inhibiting colonization by an inflammatory Bacteroides species. Resistance to Bacteroides colonization was dependent on type 2 immunity, which promoted the establishment of a protective microbiota enriched in Clostridiales. Additionally, we show that individuals from helminth-endemic regions harbor a similar protective microbiota and that deworming treatment reduced levels of Clostridiales and increased Bacteroidales. These results support a model of the hygiene hypothesis in which certain individuals are genetically susceptible to the consequences of a changing microbial environment.

https://science.sciencemag.org/content/sci/352/6285/608.full.pdf

Helminth infection promotes colonization resistance via type 2 immunity

Mice in which either the IL-4 or the IL-13 gene has been disrupted (IL-4 KO and IL-13 KO) were susceptible to infection with the intestinal nematode Trichuris muris, whereas their wild-type littermates were highly resistant and expelled the parasite. IL-4 KO mice showed diminished Th2-type responses with T. muris infection and also failed to produce parasite-specific IgG1 Abs. Although IL-13 KO mice made reduced Th2-type responses early in infection, they were capable of generating strong Th2-type responses at later time points and were unable to regulate the magnitude of their Ab isotype response. These results confirm the importance of IL-4 in resistance to T. muris and provide the first demonstration of an important role for IL-13 in resistance to helminth infection. The IL-13 KO mouse had a separate phenotype to that of the IL-4 KO mouse, suggesting that both IL-4 and IL-13 play important yet different roles in mediating immunity to intestinal helminths.

A Critical Role for IL-13 in Resistance to Intestinal Nematode Infection

After infection with the nematode Trichuris muris 70–75% of mice of the Schofield strain developed an immunity to the parasite and eliminated the worms between the 16th and 19th days after infection. In these mice the acquired immunity persisted for at least 3 months and prevented the establishment of subsequent infections. In 25–30% of the mice immunity was not produced and infections developed into mature worms. These non-resistant mice remained susceptible to further infection. The development and action of the immune response were suppressed completely by the administration of cortisone acetate.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0031182000072395

Acquired immunity to Trichuris muris in the albino laboratory mouse.

The capillariid nematodes present in passeriform hosts collected in Taiwan are recorded and described. Two new species are established, Capillaria parusi sp.n. from Parus monticolus insperatus and Sitta europaea formosana , and C. madseni sp.n. from Corvus macrorhynchus colonorum , and their affinities are discussed. Capillaria tridens, C. longifila and C. contorta are recorded from a number of new hosts.

Nematode parasites of Oceanica. IX. Capillariids from passeriform hosts collected in Taiwan.

Studies on the immunity of albino mice to Trichuris muris. Suppression of immunity by cortisone acetate.

Studies on the immunity of albino mice to Trichuris mûris. The stimulation of immunity by chemically abbreviated infections.

Three species of the nematode genus Capillaria Zeder, 1800, namely C. exilis, C. ovopunctata and C. similis, are described from material collected from the intestines of four avian hosts—Turdus merula, T. viscivorus, T. ericetorum and Sturnus vulgaris. C. similis is fully described for the first time. A consideration of these species reveals that the original description of C. exilis is inaccurate and that some revision is necessary in the systematics of this and of the other two species.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0031182000071183

D. Wakelin

Papers

Acquired immunity to Trichuris muris in the albino laboratory mouse.

Nematode parasites of Oceanica. IX. Capillariids from passeriform hosts collected in Taiwan.

Studies on the immunity of albino mice to Trichuris muris. Suppression of immunity by cortisone acetate.

Studies on the immunity of albino mice to Trichuris mûris. The stimulation of immunity by chemically abbreviated infections.

The genus Capillaria Zeder, 1800 (Nematoda) in British passerine birds.