The emerging coronavirus disease (COVID-19) caused by SARS-CoV-2 has led to social and economic disruption globally. It is urgently needed to understand the structure and function of the viral proteins for understanding of the viral infection and pathogenesis and development of prophylaxis and treatment strategies. Coronavirus non-structural protein 1 (nsp1) is a notable virulence factor with versatile roles in virus-host interactions and exhibits unique characteristics on sequence, structure, and function mode. However, the roles and characteristics of SARS-CoV-2 nsp1 are currently unclear. Here, we analyze the nsp1 of SARS-CoV-2 from the following perspectives: (1) bioinformatics analysis reveals that the novel nsp1 is conserved among SARS-CoV-2 strains and shares significant sequence identity with SARS-CoV nsp1; (2) structure modeling shows a 3D α/β-fold of SARS-CoV-2 nsp1 highly similar to that of the SARS-CoV homolog; (3) by detailed, functional review of nsp1 proteins from other coronaviruses (especially SARS-CoV) and comparison of the protein sequence and structure, we further analyzed the potential roles of SARS-CoV-2 nsp1 in manipulating host mRNA translation, antiviral innate immunity and inflammation response and thus likely promoting viral infection and pathogenesis, which are merited to be tested in the future. Finally, we discussed how understanding of the novel nsp1 may provide valuable insights into the designs of drugs and vaccines against the unprecedented coronavirus pandemic.

Bunyavirus ribonucleoprotein (RNP) that is assembled by polymerized nucleoproteins (N) coating a viral RNA and associating with a viral polymerase can be both the RNA synthesis machinery and the structural core of virions. Bunyaviral N and RNP thus could be assailable targets for host antiviral defense; however, it remains unclear which and how host factors target N/RNP to restrict bunyaviral infection. By mass spectrometry and protein-interaction analyses, we here show that host protein MOV10 targets the N proteins encoded by a group of emerging high-pathogenic representatives of bunyaviruses including severe fever with thrombocytopenia syndrome virus (SFTSV), one of the most dangerous pathogens listed by World Health Organization, in RNA-independent manner. MOV10 that was further shown to be induced specifically by SFTSV and related bunyaviruses in turn inhibits the bunyaviral replication in infected cells in series of loss/gain-of-function assays. Moreover, animal infection experiments with MOV10 knockdown corroborated the role of MOV10 in restricting SFTSV infection and pathogenicity in vivo. Minigenome assays and additional functional and mechanistic investigations demonstrate that the anti-bunyavirus activity of MOV10 is likely achieved by direct impact on viral RNP machinery but independent of its helicase activity and the cellular interferon pathway. Indeed, by its N-terminus, MOV10 binds to a protruding N-arm domain of N consisting of only 34 amino acids but proving important for N function and blocks N polymerization, N-RNA binding, and N-polymerase interaction, disabling RNP assembly. This study not only advances the understanding of bunyaviral replication and host restriction mechanisms but also presents novel paradigms for both direct antiviral action of MOV10 and host targeting of viral RNP machinery.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease caused by a novel phlebovirus, SFTS virus (SFTSV). Currently, there is no vaccine or antiviral available and the viral pathogenesis remains largely unknown. In this study, we demonstrated that SFTSV infection results in substantial production of serum interferon-γ (IFN-γ) in patients and then that IFN-γ in turn exhibits a robust anti-SFTSV activity in cultured cells, indicating the potential role of IFN-γ in anti-SFTSV immune responses. However, the IFN-γ anti-SFTSV efficacy was compromised once viral infection had been established. Consistently, we found that viral nonstructural protein (NSs) expression counteracts IFN-γ signaling. By protein interaction analyses combined with mass spectrometry, we identified the transcription factor of IFN-γ signaling pathway, STAT1, as the cellular target of SFTSV for IFN-γ antagonism. Mechanistically, SFTSV blocks IFN-γ-triggered STAT1 action through (1) NSs-STAT1 interaction-mediated sequestration of STAT1 into viral inclusion bodies and (2) viral infection-induced downregulation of STAT1 protein level. Finally, the efficacy of IFN-γ as an anti-SFTSV drug in vivo was evaluated in a mouse infection model: IFN-γ pretreatment but not posttreatment conferred significant protection to mice against lethal SFTSV infection, confirming IFN-γ's anti-SFTSV effect and viral antagonism against IFN-γ after the infection establishment. These findings present a picture of virus-host arm race and may promote not only the understanding of virus-host interactions and viral pathogenesis but also the development of antiviral therapeutics.