Background: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel batorigin CoV causing severe and fatal pneumonia in humans. Methods: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Jin Yin-tan Hospital of Wuhan, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. Results: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown b-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically 1 closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. Conclusion: A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

A novel coronavirus (2019-nCoV) was first identified in Wuhan, Hubei Province, and then spreads to the other Provinces of China. WHO decides to determine a Public Health Emergency of International Concern (PHEIC) of 2019-nCoV. 2019-nCov was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-Cov. Here based on the public single-cell RNA-Seq datasets, we analyzed the ACE2 RNA expression profile in the tissues at different locations of the respiratory tract. The result indicates that the ACE2 expression appears in nasal epithelial cells. We found that the size of this population of ACE2-expressing nasal epithelial cells is comparable with the size of the population of ACE2-expression type II alveolar cells (AT2) in the Asian sample reported by Yu Zhao et al. We further detected 2019-nCoV by polymerase chain reaction (PCR) from the nasal-swab and throat-swab of seven suspected cases. We found that 2019-nCoV tends to have a higher concentration in the nasal-swab comparing to the throat-swab, which could attribute to the ACE2-expressing nasal epithelial cells. We hope this study could be informative for virus-prevention strategy development, especially the treatment of nasal mucus. Severe infection by 2019-nCoV could result in acute respiratory distress syndrome (ARDS) and sepsis, causing death in approximately 2% of infected individuals 1 . Once contacted with the human airway, the spike proteins of 2019-nCoV can bind the surface receptors of sensitive cells, and mediate the virus to enter into target cells. Recently, Xu et.al. modeled the spike protein and indicated that Angiotensin-converting enzyme 2 (ACE2) could be the receptor for this 2019-nCoV 2 . Zhou et. al. showed that ACE2 is essential for 2019-nCov to enter HeLa cells 3. These data indicated that ACE2 is likely to be the receptor for 2019-nCov.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This “hit and run” activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites.

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