A nonredundant role for T cell-derived interleukin 22 in antibacterial defense of colonic crypts.

Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.

Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence.

Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1-3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid-distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22-producing T cells to orchestrate immune protection in the intestine.

A single-pass type I membrane protein, mannose-specific L-type lectin, potentially involved in the adhesion and invasion of Cryptosporidium parvum.

Cryptosporidium is a globally distributed zoonotic protozoan parasite that can cause severe diarrhea in humans and animals. L-type lectins are carbohydrate-binding proteins involved in multiple pathways in animals and plants, including protein transportation, secretion, innate immunity, and the unfolded protein response signaling pathway. However, the biological function of the L-type lectins remains unknown in Cryptosporidium parvum. Here, we preliminarily characterized an L-type lectin in C. parvum (CpLTL) that contains a lectin-leg-like domain. Immunofluorescence assay confirmed that CpLTL is located on the wall of oocysts, the surface of the mid-anterior region of the sporozoite and the cytoplasm of merozoites. The involvement of CpLTL in parasite invasion is partly supported by experiments showing that an anti-CpLTL antibody could partially block the invasion of C. parvum sporozoites into host cells. Moreover, the recombinant CpLTL showed binding ability with mannose and the surface of host cells, and competitively inhibited the invasion of C. parvum. Two host cell proteins were identified by proteomics which should be prioritized for future validation of CpLTL-binding. Our data indicated that CpLTL is potentially involved in the adhesion and invasion of C. parvum.

Title: Une protéine mono-transmembranaire, lectine de type L spécifique du mannose, potentiellement impliquée dans l'adhésion et l'invasion de Cryptosporidium parvum. Abstract: Cryptosporidium est un parasite protozoaire zoonotique répandu dans le monde entier qui peut provoquer de graves diarrhées chez les humains et les animaux. Les lectines de type L sont des protéines liant les glucides impliquées dans de multiples voies chez les animaux et les plantes, notamment le transport des protéines, la sécrétion, l'immunité innée et la voie de signalisation de la réponse protéique dépliée. Cependant, la fonction biologique des lectines de type L reste inconnue chez Cryptosporidium parvum. Ici, nous avons caractérisé de manière préliminaire une lectine de type L chez C. parvum (CpLTL) qui contient un domaine de type jambe de lectine. Le test d'immunofluorescence a confirmé que CpLTL est localisée sur la paroi des oocystes, la surface de la région médio-antérieure du sporozoïte et le cytoplasme des mérozoïtes. L'implication de CpLTL dans l'invasion parasitaire est en partie étayée par des expériences montrant qu'un anticorps anti-CpLTL peut bloquer partiellement l'invasion des sporozoïtes de C. parvum dans les cellules hôtes. De plus, la CpLTL recombinante a montré une capacité de liaison avec le mannose et la surface des cellules hôtes et a inhibé de manière compétitive l'invasion de C. parvum. Deux protéines de cellules hôtes ont été identifiées par protéomique et devraient être prioritaires pour la validation future de la liaison avec CpLTL. Nos données indiquent que CpLTL est potentiellement impliquée dans l'adhésion et l'invasion de C. parvum.

Antiviral innate immune response in non-myeloid cells is augmented by chloride ions via an increase in intracellular hypochlorous acid levels.

Phagocytes destroy ingested microbes by producing hypochlorous acid (HOCl) from chloride ions (Cl-) and hydrogen peroxide within phagolysosomes, using the enzyme myeloperoxidase. HOCl, the active ingredient in bleach, has antibacterial/antiviral properties. As myeloperoxidase is needed for HOCl production, non-myeloid cells are considered incapable of producing HOCl. Here, we show that epithelial, fibroblast and hepatic cells have enhanced antiviral activity in the presence of increasing concentrations of sodium chloride (NaCl). Replication of enveloped/non-enveloped, DNA (herpes simplex virus-1, murine gammaherpesvirus 68) and RNA (respiratory syncytial virus, influenza A virus, human coronavirus 229E, coxsackievirus B3) viruses are inhibited in a dose-dependent manner. Whilst treatment with sodium channel inhibitors did not prevent NaCl-mediated virus inhibition, a chloride channel inhibitor reversed inhibition by NaCl, suggesting intracellular chloride is required for antiviral activity. Inhibition is also reversed in the presence of 4-aminobenzoic hydrazide, a myeloperoxidase inhibitor, suggesting epithelial cells have a peroxidase to convert Cl- to HOCl. A significant increase in intracellular HOCl production is seen early in infection. These data suggest that non-myeloid cells possess an innate antiviral mechanism dependent on the availability of Cl- to produce HOCl. Antiviral activity against a broad range of viral infections can be augmented by increasing availability of NaCl.