Loss of Trex1 in intestinal epithelial cells prevents enteric viral infections

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B503
Abstract ID: 6281

Presenting Author:
Li Zhang , postdoc at Brown Univ.

Abstract:

The host intestinal microbiota comprises bacteria, viruses, fungi, multicellular parasites, and archaea, which directly impact host’s health. Norovirus and rotavirus are agents of acute infectious gastroenteritis with symptoms of vomiting and watery diarrhea. These viruses are restrained by interferons, especially IFN-α and IFN-λ. The Tree-prime Repair Exonuclease 1 (Trex1) is a nonprocessive 3’→5’ exonuclease that degrades cytosolic nucleic acids. Mutations in Trex1 are associated with a broad spectrum of inflammatory and autoimmune diseases. Failure to degrade cytosolic DNA activates the cGAS-STING DNA sensing pathway and ultimately drives chronic type I and III interferon signaling pathway activation. We found persistent murine norovirus (MNoV) and rotavirus infections were prevented in the Trex1^-/- mice. However, Trex1^-/-cGAS^-/- and Trex1^-/-Ifnlr1^-/- lost the protection against enteric viral infection seen in Trex1^-/- mice. Moreover, tissues from the Trex1^-/- mice exhibited a robust interferon stimulated genes (ISG) induction in response to MNoV infection compared to their WT controls. The ISG levels were dampened in both Trex1^-/-cGAS^-/- and Trex1^-/-Ifnlr1^-/- mice. Furthermore, Trex1 deficiency in gut epithelial cells is sufficient to suppress MNoV infection. In conclusion, Trex1, as a gatekeeper enzyme of the cGAS-STING pathways, has been demonstrated to be a therapeutic target to restrict enterovirus infection.