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Cryptosporidium is a leading cause of diarrheal-related deaths in children, especially in resource-poor settings. It also targets the immunocompromised, chronically infecting people living with HIV and primary immunodeficiencies. There is no vaccine or effective treatment. Although it is known from human cases and animal models that CD4+ T cells play a role in curbing Cryptosporidium , the role of CD8+ T cells remains to be defined. Using a Cryptosporidium tyzzeri mouse model, we show that gut-resident CD8+ intraepithelial lymphocytes (IELs) confer resistance to parasite growth. CD8+ IELs express and depend on the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR). AHR deficiency reduces CD8+ IELs, decreases their cytotoxicity, and worsens infection. Transfer of CD8+ IELs rescues severely immunodeficient mice from death following Cryptosporidium challenge. Finally, dietary supplementation of the AHR pro-ligand indole-3-carbinol in newborn mice promotes resistance to infection. Therefore, common dietary metabolites augment the host immune response to cryptosporidiosis, protecting against disease. [Display omitted] • CD8+ IELs control Cryptosporidium infection in mice • Anti-cryptosporidial action by CD8+ IELs requires AHR expression • IEL cytotoxic activity diminishes in the absence of AHR • IEL cytotoxic activity is augmented via AHR activation by dietary ligands Cryptosporidium causes global diarrheal disease. Maradana, Marzook, et al. discover that certain intestinal immune cells, whose survival and function rely on AHR expression, play a vital role in defending against Cryptosporidium infection. Diet supplementation with AHR ligands enhances the anti-cryptosporidial activity of these immune cells. [ABSTRACT FROM AUTHOR]

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine. [Display omitted] • Colonization of GF mice activates small intestinal eosinophils • Whole-mount microscopy of SI reveals villus blunting in the absence of eosinophils • Loss of eosinophils leads to reduced numbers of mature intestinal macrophages • Transfer of bone-marrow-derived eosinophils rescues the loss of intestinal homeostasis Eosinophils are resident cells found in high numbers in the small intestine. Ignacio et al. reveal that in response to microbial colonization, eosinophils sense the IL-33 released by epithelial cells to maintain the integrity of the intestinal villi, epithelial cell turnover, intestinal barrier function, and recruitment of mature macrophages to maintain homeostasis. [ABSTRACT FROM AUTHOR]

Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion., Competing Interests: Declaration of Interests A.L. and P.G. are shareholders in Paragen Bio Pty Ltd, a biotechnology company focusing on the use of hookworm proteins to treat inflammation., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)