| Enteroviruses (EVs) belong to the Enterovirus genus of the family Picornaviridae. The remaining seven species are known to infect humans, i.e. EV A-D and rhinovirus A-C (RV A-C). Enterovirus (EV) is an important pathogen of respiratory tract infections, detection rate ranked fourth in adults with respiratory tract infections, Seventy percent of the EV infections reported to the WHO are children below the age of 10 year. People infected with enterovirus present various clinical manifestations. In addition to asymptomatic infection, EV also cause a wide range of acute diseases, such as EV-A71 is the main pathogens that cause HFMD; Coxsackie virus can cause aseptic meningitis, pancreatitis and type I diabetes; Polio virus invades the nervous system; EV-D68 can cause moderate to severe respiratory tract infection, the main infected population is infants and adolescents; Rhinovirus (RV) is a major pathogen causes the common cold, also is the main factor of induced asthma; At present, for the treatment of EV infection is primarily supportive care, and there is no effective vaccine and broad spectrum of effects drugs. Therefore, to clarify its pathogenic mechanism so as to find effective antiviral drugs and treatment is still a problem to be solved.Previous studies indicate that innate immune evasion plays a key role in EV-D68 infection. We found that EV-D68-infected cells almost did not induce cytokine and interferon production, indicating the presence of ability of EV-D68 antagonistic innate immune. In 2015, Science reported a case of IRF7 mutation individual infected with influenza virus, cause life-threatening acute respiratory distress syndrome (ARDS), indicating IRF7 plays a very important role in the body’s defense during the invasion of the virus. Previous results from our laboratory showed that EV-A713C and can antagonize innate immune response by cleave interferon regulatory factor 7 (IRF7), through sequence alignment found EVs 3C have the same protease activity sites. Therefore, we choose other species EV representative strains, further study of EV 3C of IRF7 effect and mechanism of regulating the innate immune response, trying to clarify the generality of the common mechanism of EV antagonism innate immune. By detecting the effect of the 3C protease inhibitors and protease active site mutants toward IRF7, we found that in presence of 3C protease inhibitors can inhibit the cleavage of IRF7. Similarly, IRF7 cannot be cleavage by 3C protease activity deletion mutants, suggesting that EV-D68 3C cleavages IRF7 depends on the 3C protease activity. Our results showed that, unlike entero virus A cleavages IRF7 in Q189, enterovirus B, C, D and C rhino virus cleavage IRF7 in Q167 and Q189, besides Q167 and Q189, we first found rhinovirus A and B cleavage protein IRF7 in W130. Use EV-D68 as the representative research IRF7 affect EV replication and significance of 3C cleaving IRF7, we found that EV-D68 infection can reduce endogenous IRF7 expressions. Different cells after infection EV-D68, lead to IRF7 expression reduced with increasing the dose of virus infection in a dose-dependent decrease, while IRF3, TBK1 protein expression did not change significantly. After using lentivirus-infected cells knockdown IRF7 expression, the replication of EV-D68 enhanced. Overexpression of IRF7 could significantly inhibit EV-D68 replication, while the cleaved fragment of IRF7 cannot inhibit its replication, which reveals the EV-D68 antagonism IRF7 mediated mechanism of innate immune response.In summary, the common of enterovirus genus antagonistic innate immunity is through 3C protease cleavage IRF7 and inhibit IRF7 mediated interferon promoter activation, and thus escape the host innate immunity. Through research effect of EV 3C protease cleavage IRF7, to reveal the mechanism of inhibition of EV innate immune defense, and provided the theoretical basis for elucidating the pathogenic mechanisms of EV infection. |
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