Analysis of SARS Coronavirus-Host Cell Interactions

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DESCRIPTION (provided by applicant): Many viruses suppress host gene expression in infected cells; virus-induced host gene expression inhibition is most probably beneficial for virus replication and affects viral pathogenicity. Viral proteins that induce suppression of host gene expression are often major viral virulence factors. Severe acute respiratory syndrome (SARS) is a recently emerged human disease associated with pneumonia. A novel SARS coronavirus (SCoV) is the etiological agent of SARS. We demonstrated that SCoV nsp1 protein, which is encoded at the N-terminus of the SCoV gene 1, promotes degradation of host mRNAs, but not rRNAs, leading to strong host protein synthesis inhibition in expressing cells. Further analysis suggested that nsp1 did not promote degradation of SCoV mRNA-like mRNAs, demonstrating that SCoV nsp1 protein was the first viral protein among any known viral proteins that selectively promotes degradation of host mRNAs without affecting the stabilities of viral mRNAs. Analysis of host mRNA accumulation in SCoV-infected cells and in cells infected with SCoV carrying a mutated nsp1 that no longer suppressed host gene expression strongly suggested that nsp1 promoted host mRNA degradation in infected cells. Thus, SCoV appears to use a novel strategy to suppress host gene expression. We hypothesized that SCoV nspl promotes degradation of host mRNAs in infected cells as a means to suppress accumulation of various "hostile" host- cell proteins; to promote its own replication, SCoV may suppress antiviral proteins, like type I interferon, and proapoptotic proteins to prevent early cell death, and suppression of cellular proteins involved in both innate and acquired immunities may allow the virus to circumvent host immune recognition, and/or induction responses. Also the nsp1-induced host mRNA degradation may be beneficial for efficient translation of SCoV proteins. We suspect that nsp1 may be a major SCoV virulence factor. The present application proposes: to uncover the mechanisms of nsp1-induced host mRNA degradation using in vitro systems; to identify host proteins that interact with nsp1, which might yield clues about nsp1 selectively leading to degradation of mRNA vs. rRNA; to clarify why SCoV mRNAs were resistant to the nsp1-induced mRNA destabilization; and to examine whether some host mRNA species are also resistant to nsp1-induced host mRNA destabilization. Furthermore, we will use SCoV and its mutant carrying an altered nsp1 that no longer promotes host mRNA degradation to establish the role of nsp1 in suppressing host gene expression in infected cells.