Inhibition of NF-κB-Mediated Inflammation in Severe Acute Respiratory Syndrome Coronavirus-Infected Mice Increases Survival

Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of a respiratory disease that has a 10% mortality rate. We previously showed that SARS-CoV lacking the E gene (SARS-CoV-¿E) is attenuated in several animal model systems. Here, we show that absence of the E protein resulted in reduced expression of proinflammatory cytokines, decreased numbers of neutrophils in lung infiltrates, diminished lung pathology, and increased mouse survival, suggesting that lung inflammation contributed to SARS-CoV virulence. Further, infection with SARS-CoV-¿E resulted in decreased activation of NF-¿B compared to levels for the wild-type virus. Most important, treatment with drugs that inhibited NF-¿B activation led to a reduction in inflammation and lung pathology in both SARS-CoV-infected cultured cells and mice and significantly increased mouse survival after SARS-CoV infection. These data indicated that activation of the NF-¿B signaling pathway represents a major contribution to the inflammation induced after SARS-CoV infection and that NF-¿B inhibitors are promising antivirals in infections caused by SARS-CoV and potentially other pathogenic human coronaviruses.
This work was supported by grants from the Ministry of Science and Innovation of Spain (BIO2010-16705), the Seventh Framework Programme (FP7/2007-2013) of the European Commission (EC) under the project EMPERIE (EC grant agreement number 223498), and the U.S. National Institutes of Health (2P01AI060699-06A1 and CRIP-HHSN266200700010C). M.L.D. received a contract from the project EMPERIE (EC grant agreement number 223498), and J.A.R.-N. and C.C.-R. received a contract from Fundación La Caixa.