Background An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. MethodsIn this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done.Findings From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by nextgeneration sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats.Interpretation Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.

A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike's receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B betacoronavirus. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection.

Background A physiological small animal model that resembles COVID-19 with low mortality is lacking. Methods Molecular docking on the binding between angiotensin-converting enzyme 2 (ACE2) of common laboratory mammals and the receptor-binding domain of the surface spike protein of SARS-CoV-2 suggested that the golden Syrian hamster is an option. Virus challenge, contact transmission, and passive immunoprophylaxis were performed. Serial organ tissues and blood were harvested for histopathology, viral load and titre, chemokine/cytokine assay, and neutralising antibody titre. Results The Syrian hamster could be consistently infected by SARS-CoV-2. Maximal clinical signs of rapid breathing, weight loss, histopathological changes from the initial exudative phase of diffuse alveolar damage with extensive apoptosis to the later proliferative phase of tissue repair, airway and intestinal involvement with virus nucleocapsid protein expression, high lung viral load, and spleen and lymphoid atrophy associated with marked cytokine activation were observed within the first week of virus challenge. The lung virus titre was between 105-107 TCID50/g. Challenged index hamsters consistently infected naïve contact hamsters housed within the same cage, resulting in similar pathology but not weight loss. All infected hamsters recovered and developed mean serum neutralising antibody titre ≥1:427 fourteen days post-challenge. Immunoprophylaxis with early convalescent serum achieved significant decrease in lung viral load but not in lung pathology. No consistent non-synonymous adaptive mutation of the spike was found in viruses isolated from infected hamsters. Conclusions Besides satisfying the Koch’s postulates, this readily available hamster model is an important tool for studying transmission, pathogenesis, treatment, and vaccination against SARS-CoV-2.

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Severe acute respiratory syndrome (SARS) coronavirus is highly pathogenic in humans and evades innate immunity at multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which mobilize the front-line defense against viral infection. In this study we demonstrate that SARS coronavirus M protein inhibits gene transcription of type I interferons. M protein potently antagonizes the activation of interferon-stimulated response elementdependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKK⑀, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this element when IRF3 or IRF7 is overexpressed. M protein physically associates with RIG-I, TBK1, IKK⑀, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex and thereby inhibits TBK1/IKK⑀-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons. Severe acute respiratory syndrome (SARS)2 coronavirus causes a highly lethal infectious disease in humans characterized by an aberrant immune response (1). The production and action of type I interferons, which are major components of antiviral innate immunity (2, 3), are inhibited at multiple levels by SARS coronavirus (4, 5). This inhibition is thought to be mediated through viral structural and nonstructural proteins N, ORF3b, ORF6, nsp1, and papain-like protease (6 -12).The signaling pathways through which viruses induce the production of type I interferons have been well characterized (13)(14)(15). In response to double-stranded RNA (dsRNA) produced during viral replication, endosomal Toll-like receptor 3 (TLR3) and cytoplasmic retinoic acid-inducible gene I (RIG-I) trigger the activation of two different pathways adapted to downstream kinases through TRIF (TLR adaptor inducing interferon ␤) and VISA, respectively. These pathways converge on the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex, which catalyzes the phosphorylation of IRF3 and IRF7 transcription factors, leading to the activation of type I interferon promoters (15-17).SARS coronaviral proteins counteract the production of type I interferons at multiple steps. Although IRF3 phosphorylation was inhibited in cells expressing ORF3b, ORF6, or N protein (7), papain-like protease could physically interact with IRF3 and prevent its phosphorylation and nuclear translocation in a protease-independent manner (11). In addition, nsp1 suppressed the synthesis of host proteins including interferons by inducing mRNA degradation (6, 12). Meanwhile, viral proteins such as nsp1 and ORF6 were multifunctional (10,18,19) and could also inhibit interferon signaling. For example, both nsp1 and ORF6 inhibited the activity of STAT1, a key regulator of interferon-responsive genes (8, 9). Whereas nsp1 attenuated phosphorylati...