Hepatovirus 3ABC proteases and evolution of mitochondrial antiviral signaling protein (MAVS)

• Published in: Journal of hepatology Vol. 71; no. 1; pp. 25 - 34
• Main Authors: Feng, Hui, Sander, Anna-Lena, Moreira-Soto, Andrés, Yamane, Daisuke, Drexler, Jan Felix, Lemon, Stanley M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2019
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Chymotrypsin-like protease; Cross-species transmission; Evolution, Molecular; HEK293 Cells; hepatitis A virus; Hepatitis A virus - genetics; Hepatitis A virus - immunology; Humans; Immunity, Innate - immunology; Innate immunity; Signal Transduction - physiology; Viral Nonstructural Proteins - metabolism; Viral Proteases - metabolism; Virus evolution; Virus Replication - physiology; Innate immunity; Virus evolution; hepatitis A virus; Chymotrypsin-like protease; Cross-species transmission
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2019.02.020

[Display omitted] •3ABC proteases expressed by bat hepatoviruses cleave human MAVS at Glu463/Gly464.•Bat hepatovirus 3ABC proteases disrupt viral activation of interferon-β in human cells.•MAVS orthologs from rodents and bats resist cleavage by cognate hepatovirus 3ABC proteases.•Bat and rodent MAVS orthologs have been subject to diversifying selection at 3ABC cleavage sites.•Cross-species disruption of MAVS signaling by 3ABC may facilitate hepatovirus host species shifts. Unlike 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. We 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. 3ABC 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. 3ABC 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. Hepatitis 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.