Cryptosporidium parvum infects intestinal epithelial cells and is commonly the parasite species involved in mammalian cryptosporidiosis, a major health problem for humans and neonatal livestock. In mice, immunologically mediated elimination of C. parvum requires CD4+ T cells and IFN-γ. However, innate immune responses also have a significant protective role in both adult and neonatal mice. NK cells and IFN-γ have been shown to be important components in immunity in T and B cell-deficient mice, but IFN-γ-dependent resistance has also been demonstrated in alymphocytic mice. Epithelial cells may play a vital role in immunity as once infected these cells have increased expression of inflammatory chemokines and cytokines and demonstrate antimicrobial killing mechanisms, including production of NO and antimicrobial peptides. Toll-like receptors facilitate the establishment of immunity in mice and are involved in the development of inflammatory responses of infected epithelial cells and also dendritic cells.

A gamma interferon (IFN-␥)-dependent innate immune response operates against the intestinal parasiteCryptosporidium parvum in T-and B-cell-deficient SCID mice. Although NK cells are a major source of IFN-␥ in innate immunity, their protective role against C. parvum has been unclear. The role of NK cells in innate immunity was investigated using Rag2 ؊/؊ mice, which lack T and B cells, and Rag2 ؊/؊ ␥ c ؊/؊ mice, which, in addition, lack NK cells. Adult mice of both knockout lines developed progressive chronic infections; however, on most days the level of oocyst excretion was higher in Rag2 ؊/؊ ␥ c ؊/؊ mice and these animals developed morbidity and died, whereas within the same period the Rag2 ؊/؊ mice appeared healthy. Neonatal mice of both mouse lines survived a rapid onset of infection that reached a higher intensity in Rag2 ؊/؊ ␥ c ؊/؊ mice. Significantly, similar levels of intestinal IFN-␥ mRNA were expressed in Rag2 ؊/؊ and Rag2 ؊/؊ ␥ c ؊/؊ mice. Also, infections in each mouse line were exacerbated by treatment with anti-IFN-␥ neutralizing antibodies.

Type II interferon (IFN), IFN-gamma, is important in innate immunity to the intestinal protozoan parasite Cryptosporidium species, which infects epithelial cells (enterocytes). This investigation is, to our knowledge, the first to characterize the role of type I IFN in innate immunity to this parasite. Pretreatment of human or murine enterocyte cell lines with IFN-alpha/beta inhibited parasite development, and we identified that a key mechanism of cytokine action was to prevent parasite invasion of enterocytes. IFN-alpha/beta was rapidly expressed by infected murine enterocytes and also by bone marrow-derived dendritic cells that were exposed to live parasites. Treatment of neonatal severe combined immunodeficiency mice with anti-IFN-alpha/beta neutralizing antibodies before infection increased oocyst reproduction, as measured at the peak of infection, and parasite numbers in gut epithelium were also increased 2 days after infection. The latter observation correlated with strong intestinal expression of both IFN-alpha and IFN-beta messenger RNA within 24 h after infection. Treatment with anti-IFN-alpha/beta, however, did not reduce early expression of IFN-gamma. These findings identify a novel early innate host response against Cryptosporidium parvum involving IFN-alpha/beta.

Cryptosporidiosis is an important diarrheal disease of humans and neonatal livestock caused by؊/؊ mice around the peak of infection, but IL-10 expression was also higher in WT mice. These results suggest that although CD4 ؉ T cells may be important for elimination of C. parvum, these cells are dispensable for controlling the early acute phase of infection in neonates.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exomesequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10 −10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 −10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.