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The parasitic helminth Trichinella spiralis, which poses a serious health risk to animals and humans, can be found worldwide. Recent findings indicate that a rare type of gut epithelial cell, tuft cells, can detect the helminth, triggering type 2 immune responses. However, the underlying molecular mechanisms remain to be fully understood. Here we show that both excretory–secretory products (E–S) and extract of T. spiralis can stimulate the release of the cytokine interleukin 25 (IL-25) from the mouse small intestinal villi and evoke calcium responses from tuft cells in the intestinal organoids, which can be blocked by a bitter-taste receptor inhibitor, allyl isothiocyanate. Heterologously expressed mouse Tas2r bittertaste receptors, the expression of which is augmented during tuftcell hyperplasia, can respond to the E–S and extract as well as to the bitter compound salicin whereas salicin in turn can induce IL-25 release from tuft cells. Furthermore, abolishment of the G-protein γ13 subunit, application of the inhibitors for G-protein αo/i, Gβγ subunits, and phospholipase Cβ2 dramatically reduces the IL-25 release. Finally, tuft cells are found to utilize the inositol triphosphate receptor type 2 (Ip₃r2) to regulate cytosolic calcium and thus Trpm5 activity, while potentiation of Trpm5 by a sweet-tasting compound, stevioside, enhances tuft cell IL-25 release and hyperplasia in vivo. Taken together, T. spiralis infection activates a signaling pathway in intestinal tuft cells similar to that of taste-bud cells, but with some key differences, to initiate type 2 immunity.

“Taste-like” tuft cells in the intestine trigger type 2 immunity in response toworm infection. The secretion of interleukin-13 (IL-13) from type 2 innate lymphoid cells (ILC2) represents a key step in the tuft cell–ILC2 cell–intestinal epithelial cell circuit that drives the clearance of worms from the gut via type 2 immune responses. Hallmark features of type 2 responses include tissue remodeling, such as tuft and goblet cell expansion, and villus atrophy, yet it remains unclear if additional molecular changes in the gut epithelium facilitate the clearance of worms from the gut. Using gut organoids, we demonstrated that IL-4 and IL-13, two type 2 cytokines with similar functions, not only induced the classical type 2 responses (e.g., tuft cell expansion) but also drastically up-regulated the expression of gasdermin C genes (Gsdmcs). Using an in vivo worm-induced type 2 immunity model, we confirmed the up-regulation of Gsdmcs in Nippostrongylus brasiliensis–infected wild-type C57BL/6 mice. Consistent with gasdermin family members being principal effectors of pyroptosis, overexpression of Gsdmc2 in human embryonic kidney 293 (HEK293) cells triggered pyroptosis and lytic cell death. Moreover, in intestinal organoids treated with IL-4 or IL-13, or in wild-type mice infected with N. brasiliensis, lytic cell death increased, which may account for villus atrophy observed in worm-infected mice. Thus, we propose that the up-regulated Gsdmc family may be major effectors for type 2 responses in the gut and that Gsdmc-mediated pyroptosis may provide a conduit for the release of antiparasitic factors from enterocytes to facilitate the clearance of worms.

Objective Ascaris -induced small bowel obstruction (SBO) is a common sequel of Ascaris lumbricoides (AL) infestation. Most cases respond to conservative treatment practiced in different centers worldwide. We conceived a prospective randomized trial to compare the conservative treatment with gastrografin administered in addition to the conservative treatment. Study design This prospective randomized study was conducted between January 2011 and June 2014 at Department of Paediatric and Neonatal Surgery, a tertiary-care hospital. Patients were divided into two groups, one group received conservative treatment and the other received gastrografin in addition to conservative treatment. Forty patients having uncomplicated AL-induced SBO were included in each group. Gastrografin was administered through nasogastric tube and serial clinical and radiological monitoring was performed. The duration of hospital stay, time between admission and first oral feed, passage of worms/flatus were compared in the two groups. Student’s t test was used for comparing these variables. Results Average time for passage of flatus or worms and resolution of abdominal signs and was shorter in gastrografin group as compared to the conservative group. This difference was found to be statistically significant. The average duration of hospital stay in gastrografin group was 25.20 ± 8.01 h whereas it was 61.12 ± 14.64 h in the conservative group ( P  < 0.001). The difference in the operation rate was statistically insignificant (2 in gastrografin group and 3 in the conservative group).No serious adverse reaction was noted after gastrografin administration. Conclusion Use of gastrografin resulted in faster relief of signs and symptoms of AL-induced SBO, early passage of worms/flatus and return to oral feeds. However, the role of gastrografin role in reducing the likelihood of laparotomy remains inconclusive. Adverse effects of gastrografin can be prevented if it is used in well-hydrated patients.

Stem-cell-derived organoids recapitulate in vivo physiology of their original tissues, representing valuable systems to model medical disorders such as infectious diseases. Cryptosporidium , a protozoan parasite, is a leading cause of diarrhoea and a major cause of child mortality worldwide. Drug development requires detailed knowledge of the pathophysiology of Cryptosporidium , but experimental approaches have been hindered by the lack of an optimal in vitro culture system. Here, we show that Cryptosporidium can infect epithelial organoids derived from human small intestine and lung. The parasite propagates within the organoids and completes its complex life cycle. Temporal analysis of the Cryptosporidium transcriptome during organoid infection reveals dynamic regulation of transcripts related to its life cycle. Our study presents organoids as a physiologically relevant in vitro model system to study Cryptosporidium infection. The parasite Cryptosporidium can infect human organoids, where it replicates and completes its complex lifecycle. This new in vitro system enables the study of parasite development within the host and associated immune responses.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis . Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca 2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity. P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca 2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

Recognizing that enteric tuft cells can signal the presence of nematode parasites, we investigated whether tuft cells are required for the expulsion of the cestode, Hymenolepis diminuta , from the non-permissive mouse host, and in concomitant anti-helminthic responses. BALB/c and C57BL/6 mice infected with H . diminuta expelled the worms by 11 days post-infection (dpi) and displayed DCLK1 + (doublecortin-like kinase 1) tuft cell hyperplasia in the small intestine (not the colon) at 11 dpi. This tuft cell hyperplasia was dependent on IL-4R α signalling and adaptive immunity, but not the microbiota. Expulsion of H . diminuta was slowed until at least 14 dpi, but not negated, in tuft cell-deficient Pou2f3 -/- mice and was accompanied by delayed goblet cell hyperplasia and slowed small bowel transit. Worm antigen and mitogen evoked production of IL-4 and IL-10 by splenocytes from wild-type and Pou2f3 -/- mice was not appreciably different, suggesting similar systemic immune reactivity to infection with H . diminuta . Wild-type and Pou2f3 -/- mice infected with H . diminuta displayed partial protection against subsequent infection with the nematode Heligmosomoides bakeri . We speculate that, with respect to H . diminuta , enteric tuft cells are important for local immune events driving the rapidity of H . diminuta expulsion but are not critical in initiating or sustaining systemic Th2 responses that provide concomitant immunity against secondary infection with H . bakeri .

Parasitic nematodes are potent modulators of immune reactivity in mice and men. Intestinal nematodes live in close contact with commensal gut bacteria, provoke biased Th2 immune responses upon infection, and subsequently lead to changes in gut physiology. We hypothesized that murine nematode infection is associated with distinct changes of the intestinal bacterial microbiota composition. We here studied intestinal inflammatory and immune responses in mice following infection with the hookworm Heligmosomoides polygyrus bakeri and applied cultural and molecular techniques to quantitatively assess intestinal microbiota changes in the ileum, cecum and colon. At day 14 post nematode infection, mice harbored significantly higher numbers of γ-Proteobacteria/Enterobacteriaceae and members of the Bacteroides/Prevotella group in their cecum as compared to uninfected controls. Abundance of Gram-positive species such as Lactobacilli, Clostridia as well as the total bacterial load was not affected by worm infection. The altered microbiota composition was independent of the IL-4/-13 - STAT6 signaling axis, as infected IL-4Rα(-/-) mice showed a similar increase in enterobacterial loads. In conclusion, infection with an enteric nematode is accompanied by distinct intestinal microbiota changes towards higher abundance of gram-negative commensal species at the small intestinal site of infection (and inflammation), but also in the parasite-free large intestinal tract. Further studies should unravel the impact of nematode-induced microbiota changes in inflammatory bowel disease to allow for a better understanding of how theses parasites interfere with intestinal inflammation and bacterial communities in men.

The pathology of schistosomiasis mansoni, a neglected tropical disease of great clinical and socioeconomic importance, results from the parasite eggs that become trapped in host tissues, particularly in the liver and intestines. Continuous antigenic stimulation from these eggs leads to recruitment of inflammatory cells to the sites of infection with formation of periovular granulomas. These complex structures have variable size and composition and are the most striking histopathological feature of schistosomiasis mansoni. However, evaluation of granulomas by conventional microscopy methods is time-consuming and limited, especially in large-scale studies. Here, we used high resolution Whole Slide Imaging (WSI), which allows fast scanning of entire histological slides, and multiple morphometric evaluations, to assess the granulomatous response elicited in target organs (liver, small and large intestines) of two models of schistosomiasis mansoni. One of the advantages of WSI, also termed virtual microscopy, is that it generates images that simultaneously offer high resolution and a wide field of observation. By using a model of natural (Nectomys squamipes, a wild reservoir captured from endemic areas in Brazil) and experimental (Swiss mouse) infection with Schistosoma mansoni, we provided the first detailed WSI characterization of granulomas and other pathological aspects. WSI and quantitative analyses enabled a fast and reliable assessment of the number, evolutional types, frequency and areas of granulomas and inflammatory infiltrates and revealed that target organs are differentially impacted by inflammatory responses in the natural and experimental infections. Remarkably, high-resolution analysis of individual eosinophils, key cells elicited by this helminthic infection, showed a great difference in eosinophil numbers between the two infections. Moreover, features such as the intestinal egg path and confluent granulomas were uncovered. Thus, WSI may be a suitable tool for detailed and precise histological analysis of granulomas and other pathological aspects for clinical and research studies of schistosomiasis.

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.

Early abortion is a clinical presentation of ovine toxoplasmosis that occurs in the second week post-infection (pi), which is characterised by placental infarcts, foetal leukomalacia and absence of parasites in the placenta and foetal tissues. The pathogenic mechanism of early abortion is unknown , and descriptions of the early dynamics of T. gondii infection in pregnant sheep are scarce. The aim of this study was to investigate the presence of lesions and parasite DNA in the small intestine, mesenteric lymph nodes and placenta/foetus, that could be key during the first week after oral infection in sheep at mid-pregnancy. In the small intestine, lesions were rare and parasite DNA detection rates were low (3–8%), with the highest parasite DNA detection and burden found on day 6 pi in the Peyer’s patches of the medial jejunum. In the mesenteric lymph nodes, adenomegaly and microscopic lesions were mainly observed on day 6 pi. Parasite DNA was detected in 11% and 61.2% of the samples from mesenteric lymph nodes on days 3 and 6 pi, respectively, with higher parasite DNA detection rates and burdens in the medial and distal jejunal lymph nodes on day 6 pi. In the placentomes, on day 6 pi, gross lesions were not observed, although significant histological changes, such as endothelial activation and vascular thrombosis, were found in 18.6% and 8.3% of the placentomes, respectively. These findings lay the groundwork for future research aimed at elucidating the precise mechanisms underlying early abortions following T. gondii infection in pregnant sheep.