Enterovirus71Targets MAVS To Inhibit Anti-Viral Type Ⅰ Interferon Responses

Enterovirus71(EV71), is the major causative pathogen of hand, foot, and mouth disease (HFMD). Acute EV71infection can also induce severe neurological disease, including aseptic meningitis, brainstem and/or cerebellar encephalitis, and acute flaccid paralysis. In recent years, the frequency and the severity of EV71infection are increasing in China and pose a threat to human health and social stability.Although the specific molecular mechanism underlying EV71pathogenesis is not clear, EV71virulence is associated with circumventing anti-viral immunity. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins.Therefore, this study aimed to fully investigate the antagonistic mechanisms of EV71act on host anti-viral innate immunity. Through evaluating type-I interferon production on different levels, we determined the inhibition occurs upstream of IRF3(interferon regulatory factor3) activation. Further study showed that EV71inhibits anti-viral type I interferon responses by targeting the mitochondrial anti-viral signaling protein (MAVS) upstream of type I interferon production. EV71infection induced MAVS cleavage and the cleavage fragments were released from mitochondria into the cytoplasm. When host cell mechanisms and viral proteases were examined respectively, we found it was viral2A protease (2Apro) mediated the MAVS cleavage. The Protease-Glo assay on constituted peptides of extra-membrane region of MAVS and verification using in vitro cleavage assay revealed that MAVS was cleaved at3residues between the proline-rich and trans-membrane domains:they were Gly209, Gly251and Gly265. Although2Apro exhibits different proteolysis activity on these three cleavage residues, the resulting fragmentation all effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71infection also induced morphologic and functional changes to the mitochondria and EV71viral protein partially co-localization with it. Through isolation and purification of mitochondria, EV71structural protein VP1was detected on purified mitochondrial components, suggesting not only a novel role for mitochondria in the EV71replication cycle but also an explanation of how EV71-derived2Apro could approach MAVS.Taken together, our findings reveal a novel strategy employed by EV71to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms, provding basic knowledge for revealing the pathogenic mechanisms of EV71.