Mutation and adaptation have driven the co-evolution of coronaviruses (CoVs) and their hosts, including human beings, for thousands of years. Before 2003, two human CoVs (HCoVs) were known to cause mild illness, such as common cold. The outbreaks of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) have flipped the coin to reveal how devastating and lifethreatening an HCoV infection could be. The emergence of SARS-CoV-2 in central China at the end of 2019 has thrusted CoVs into the spotlight again and surprised us with its high transmissibility but reduced pathogenicity compared to its sister SARS-CoV. HCoV infection is a zoonosis and understanding the zoonotic origins of HCoVs would serve us well. Most HCoVs originated from bats where they are non-pathogenic. The intermediate reservoir hosts of some HCoVs are also known. Identifying the animal hosts has direct implications in the prevention of human diseases. Investigating CoV-host interactions in animals might also derive important insight on CoV pathogenesis in humans. In this review, we present an overview of the existing knowledge about the seven HCoVs, with a focus on the history of their discovery as well as their zoonotic origins and interspecies transmission. Importantly, we compare and contrast the different HCoVs from a perspective of virus evolution and genome recombination. The current CoV disease 2019 (COVID-19) epidemic is discussed in this context. In addition, the requirements for successful host switches and the implications of virus evolution on disease severity are also highlighted.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing global health emergency. Here we highlight nine most important research questions concerning virus transmission, asymptomatic and presymptomatic virus shedding, diagnosis, treatment, vaccine development, origin of virus and viral pathogenesis.

Severe acute respiratory syndrome Coronavirus (SARS‐CoV) is capable of inducing a storm of proinflammatory cytokines. In this study, we show that the SARS‐CoV open reading frame 3a (ORF3a) accessory protein activates the NLRP3 inflammasome by promoting TNF receptor‐associated factor 3 (TRAF3)–mediated ubiquitination of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). SARS‐CoV and its ORF3a protein were found to be potent activators of pro–IL‐1β gene transcription and protein maturation, the 2 signals required for activation of the NLRP3 inflammasome. ORF3a induced pro–IL‐1β transcription through activation of NF‐κB, which was mediated by TRAF3‐dependent ubiquitination and processing of p105. ORF3a‐induced elevation of IL‐1β secretion was independent of its ion channel activity or absent in melanoma 2 but required NLRP3, ASC, and TRAF3. ORF3a interacted with TRAF3 and ASC, colocalized with them in discrete punctate structures in the cytoplasm, and facilitated ASC speck formation. TRAF3‐dependent K63‐linked ubiquitination of ASC was more pronounced in SARS‐CoV–infected cells or when ORF3a was expressed. Taken together, our findings reveal a new mechanism by which SARS‐CoV ORF3a protein activates NF‐κB and the NLRP3 inflammasome by promoting TRAF3‐dependent ubiquitination of p105 and ASC.—Siu, K.‐L., Yuen, K.‐S., Castano‐Rodriguez, C., Ye, Z.‐W., Yeung, M.‐L., Fung, S.‐Y., Yuan, S., Chan, C.‐P., Yuen, K.‐Y., Enjuanes, L., Jin, D.‐Y. Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3‐dependent ubiquitination of ASC. FASEB J. 33, 8865–8877 (2019). http://www.fasebj.org

World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed. ARTICLE HISTORY

Middle East respiratory syndrome coronavirus (MERS-CoV

Coronaviruses have developed various measures to evade innate immunity. We have previously shown that severe acute respiratory syndrome (SARS) coronavirus M protein suppresses type I interferon (IFN) production by impeding the formation of functional TRAF3-containing complex. In this study, we demonstrate that the IFN-antagonizing activity is specific to SARS coronavirus M protein and is mediated through its first transmembrane domain (TM1) located at the N terminus. M protein from human coronavirus HKU1 does not inhibit IFN production. Whereas N-linked glycosylation of SARS coronavirus M protein has no influence on IFN antagonism, TM1 is indispensable for the suppression of IFN production. TM1 targets SARS coronavirus M protein and heterologous proteins to the Golgi apparatus, yet Golgi localization is required but not sufficient for IFN antagonism. Mechanistically, TM1 is capable of binding with RIG-I, TRAF3, TBK1 and IKKe, and preventing the interaction of TRAF3 with its downstream effectors. Our work defines the molecular architecture of SARS coronavirus M protein required for suppression of innate antiviral response.

Middle East respiratory syndrome coronavirus (MERS-CoV) infection has claimed hundreds of lives and has become a global threat since its emergence in Saudi Arabia in 2012. The ability of MERS-CoV to evade the host innate antiviral response may contribute to its severe pathogenesis. Many MERS-CoV-encoded proteins were identified to have interferon (IFN)-antagonizing properties, which correlates well with the reduced IFN levels observed in infected patients and ex vivo models. In this study, we fully characterized the IFN-antagonizing property of the MERS-CoV M protein. Expression of MERS-CoV M protein suppressed type I IFN expression in response to Sendai virus infection or poly(I:C) induction. This suppressive effect was found to be specific for the activation of IFN regulatory factor 3 (IRF3) but not nuclear factor-κB. MERS-CoV M protein interacted with TRAF3 and disrupted TRAF3–TBK1 association leading to reduced IRF3 activation. M proteins from MERS-CoV and SARS-CoV have three highly similar conserved N-terminal transmembrane domains and a C-terminal region. Using chimeric and truncation mutants, the N-terminal transmembrane domains of the MERS-CoV M protein were found to be sufficient for its inhibitory effect on IFN expression, whereas the C-terminal domain was unable to induce this suppression. Collectively, our findings suggest a common and conserved mechanism through which highly pathogenic MERS-CoV and SARS-CoV harness their M proteins to suppress type I IFN expression at the level of TBK1-dependent phosphorylation and activation of IRF3 resulting in evasion of the host innate antiviral response.

Severe complications of Zika virus (ZIKV) infection might be caused by inflammation, but how ZIKV induces proinflammatory cytokines is not understood. In this study, we show opposite regulatory effects of the ZIKV NS5 protein on interferon (IFN) signaling. Whereas ZIKV and its NS5 protein were potent suppressors of type I and type III IFN signaling, they were found to activate type II IFN signaling. Inversely, IFN-␥ augmented ZIKV replication. NS5 interacted with STAT2 and targeted it for ubiquitination and degradation, but it had no influence on STAT1 stability or nuclear translocation. The recruitment of STAT1-STAT2-IRF9 to IFN-␤-stimulated genes was compromised when NS5 was expressed. Concurrently, the formation of STAT1-STAT1 homodimers and their recruitment to IFN-␥-stimulated genes, such as the gene encoding the proinflammatory cytokine CXCL10, were augmented. Silencing the expression of an IFN-␥ receptor subunit or treatment of ZIKV-infected cells with a JAK2 inhibitor suppressed viral replication and viral induction of IFN-␥-stimulated genes. Taken together, our findings provide a new mechanism by which the ZIKV NS5 protein differentially regulates IFN signaling to facilitate viral replication and cause diseases. This activity might be shared by a group of viral IFN modulators.IMPORTANCE Mammalian cells produce three types of interferons to combat viral infection and to control host immune responses. To replicate and cause diseases, pathogenic viruses have developed different strategies to defeat the action of host interferons. Many viral proteins, including the Zika virus (ZIKV) NS5 protein, are known to be able to suppress the antiviral property of type I and type III interferons. Here we further show that the ZIKV NS5 protein can also boost the activity of type II interferon to induce cellular proteins that promote inflammation. This is mediated by the differential effect of the ZIKV NS5 protein on a pair of cellular transcription factors, STAT1 and STAT2. NS5 induces the degradation of STAT2 but promotes the formation of STAT1-STAT1 protein complexes, which activate genes controlled by type II interferon. A drug that specifically inhibits the IFN-␥ receptor or STAT1 shows an anti-ZIKV effect and might also have anti-inflammatory activity.KEYWORDS Zika virus, NS5 protein, type II interferon, STAT1, STAT2 Z ika virus (ZIKV) is a member of the Flaviviridae family with a positive-sense RNA genome of about 10 kb (1). Similar to other flaviviruses, such as yellow fever virus, dengue virus, and Japanese encephalitis virus, ZIKV expresses a single polypeptide which is proteolytically processed into 3 structural (C, prM, and E) and 7 nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. ZIKV is an arbovirus transmitted to humans through the bites of mosquitoes of the species Aedes aegypti and, to a lesser extent, Aedes albopictus (2). Since its discovery in 1947 (3), ZIKV had been known to cause only mild and self-limiting febrile diseases, with a majority of patients being