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Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis.

ABSTRACT: RIG-I-like receptors (RLRs) activate host innate immune responses against virus infection through recruiting the mitochondrial adaptor protein MAVS (also known as IPS1, VISA, or CARDIF). Here we show that MAVS also plays a pivotal role in maintaining intestinal homeostasis. We found that MAVS knockout mice developed more severe mortality and morbidity than WT animals in an experimental model of colitis. Bone marrow transplantation experiments revealed that MAVS in cells of nonhematopoietic origin plays a dominant role in the protection against colitis. Importantly, RNA species derived from intestinal commensal bacteria activate the RIG-I-MAVS pathway to induce the production of multiple cytokines and antimicrobial peptides, including IFN-? and RegIII?. These results unveil a previously unexplored role of MAVS in monitoring intestinal commensal bacteria and maintaining tissue homeostasis.

SUBMITTER: Li XD

PROVIDER: S-EPMC3198352 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis.

Li Xiao-Dong XD Chiu Yu-Hsin YH Ismail Anisa S AS Behrendt Cassie L CL Wight-Carter Mary M Hooper Lora V LV Chen Zhijian J ZJ

Proceedings of the National Academy of Sciences of the United States of America 20110929 42

RIG-I-like receptors (RLRs) activate host innate immune responses against virus infection through recruiting the mitochondrial adaptor protein MAVS (also known as IPS1, VISA, or CARDIF). Here we show that MAVS also plays a pivotal role in maintaining intestinal homeostasis. We found that MAVS knockout mice developed more severe mortality and morbidity than WT animals in an experimental model of colitis. Bone marrow transplantation experiments revealed that MAVS in cells of nonhematopoietic origi ...[more]

PMID: 21960441

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Project description:Background & aimsUnlike other hepatitis viruses that have infected primates for millions of years, hepatitis A virus (HAV) likely entered human populations only 10-12 thousand years ago after jumping from a rodent host. The phylogeny of modern hepatoviruses that infect rodents and bats suggest that multiple similar host shifts have occurred in the past. The factors determining such shifts are unknown, but the capacity to overcome innate antiviral responses in a foreign species is likely key.MethodsWe assessed the capacity of diverse hepatovirus 3ABC proteases to cleave mitochondrial antiviral signaling protein (MAVS) and disrupt antiviral signaling in HEK293 and human hepatocyte-derived cell lines. We also applied maximum-likelihood and Bayesian algorithms to identify sites of diversifying selection in MAVS orthologs from 75 chiropteran, rodent and primate species.Results3ABC proteases from bat, but not rodent hepatoviruses efficiently cleaved human MAVS at Glu463/Gly464, disrupting virus activation of the interferon-β promoter, whereas human HAV 3ABC cleaved at Gln427/Val428. In contrast, MAVS orthologs from rodents and bats were resistant to cleavage by 3ABC proteases of cognate hepatoviruses and in several cases human HAV. A search for diversifying selection among MAVS orthologs from all 3 orders revealed 90 of ∼540 residues to be under positive selection, including residues in chiropteran MAVS that align with the site of cleavage of human MAVS by bat 3ABC proteases.Conclusions3ABC protease cleavage of MAVS is a conserved attribute of hepatoviruses, acting broadly across different mammalian species and associated with evidence of diversifying selection at cleavage sites in rodent and bat MAVS orthologs. The capacity of hepatoviruses to disrupt MAVS-mediated innate immune responses has shaped evolution of both hepatoviruses and their hosts, and facilitates cross-species transmission of hepatitis A.Lay summaryHepatitis A virus, a common cause of acute hepatitis globally, is likely to have evolved from a virus that jumped from a rodent species to humans within the last 10-12 thousand years. Here we show that distantly related hepatoviruses, that infect bats and rodents today, express proteases that disrupt innate antiviral responses in human cells. This conserved attribute of hepatoviruses may have contributed to that ancient host species shift.

Dataset Information

Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis.

Publications

Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis.

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