Key result
Enterovirus D68 inhibits innate antiviral immunity through its 3C protease, which cleaves and inactivates interferon regulatory factor 7 (IRF7) to suppress type I interferon expression.
EV-D68 evades innate antiviral immunity by using its 3C protease to cleave and inactivate IRF7, suppressing type I interferon responses.
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May guide antiviral targeting of EV-D68 3C protease; leaves open translation from animal models to human disease.
UNLABELLED: Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C(pro), an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C(pro) targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C(pro). Together, these results suggest that a dynamic interplay between 3C(pro) and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE: EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C(pro)-IRF7 interaction may represent an interface that dictates EV-D68 infection.
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Xiang et al. (2015) studied Enterovirus D68 infection. Enterovirus D68 3C protease vs. Mock infection or control plasmids was evaluated on Cleavage of IRF7 and inhibition of type I interferon expression. Enterovirus D68 inhibits innate antiviral immunity through its 3C protease, which cleaves and inactivates interferon regulatory factor 7 (IRF7) to suppress type I interferon expression.
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