title: Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, National Center of Biotechnology, Campus Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Marta L
authors.initials: ML
authors.lastname: DeDiego
authors.forename: Jose L
authors.initials: JL
authors.lastname: Nieto-Torres
authors.forename: Jose A
authors.initials: JA
authors.lastname: Regla-Nava
authors.forename: Jose M
authors.initials: JM
authors.lastname: Jimenez-Guardeño
authors.forename: Raul
authors.initials: R
authors.lastname: Fernandez-Delgado
authors.forename: Craig
authors.initials: C
authors.lastname: Fett
authors.forename: Carlos
authors.initials: C
authors.lastname: Castaño-Rodriguez
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
authors.forename: Luis
authors.initials: L
authors.lastname: Enjuanes
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics / Q000276:immunology* / Q000401:mortality* / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D016207:Cytokines; C501689:E protein, SARS coronavirus; D016328:NF-kappa B; D014759:Viral Envelope Proteins; D000086082:Viroporin Proteins