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Publication : A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition.

First Author  Gibson AR Year  2022
Journal  PLoS Pathog Volume  18
Issue  5 Pages  e1010003
PubMed ID  35584177 Mgi Jnum  J:338965
Mgi Id  MGI:7283437 Doi  10.1371/journal.ppat.1010003
Citation  Gibson AR, et al. (2022) A genetic screen identifies a protective type III interferon response to Cryptosporidium that requires TLR3 dependent recognition. PLoS Pathog 18(5):e1010003
abstractText  Cryptosporidium is a leading cause of severe diarrhea and diarrheal-related death in children worldwide. As an obligate intracellular parasite, Cryptosporidium relies on intestinal epithelial cells to provide a niche for its growth and survival, but little is known about the contributions that the infected cell makes to this relationship. Here we conducted a genome wide CRISPR/Cas9 knockout screen to discover host genes that influence Cryptosporidium parvum infection and/or host cell survival. Gene enrichment analysis indicated that the host interferon response, glycosaminoglycan (GAG) and glycosylphosphatidylinositol (GPI) anchor biosynthesis are important determinants of susceptibility to C. parvum infection and impact on the viability of host cells in the context of parasite infection. Several of these pathways are linked to parasite attachment and invasion and C-type lectins on the surface of the parasite. Evaluation of transcript and protein induction of innate interferons revealed a pronounced type III interferon response to Cryptosporidium in human cells as well as in mice. Treatment of mice with IFNlambda reduced infection burden and protected immunocompromised mice from severe outcomes including death, with effects that required STAT1 signaling in the enterocyte. Initiation of this type III interferon response was dependent on sustained intracellular growth and mediated by the pattern recognition receptor TLR3. We conclude that host cell intrinsic recognition of Cryptosporidium results in IFNlambda production critical to early protection against this infection.
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