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-ΔE) 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-ΔE resulted in decreased activation of NF-κB compared to levels for the wild-type virus. Most important, treatment with drugs that inhibited NF-κB 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-κB signaling pathway represents a major contribution to the inflammation induced after SARS-CoV infection and that NF-κB inhibitors are promising antivirals in infections caused by SARS-CoV and potentially other pathogenic human coronaviruses.
