The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-β promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-β treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing1–3. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence4,5, a form of terminal cell cycle arrest associated with pro-inflammatory responses6. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Highlights d BALF cell transcriptome indicates robust innate immune responses in COVID-19 patients d COVID-19 patients exhibit chemokine-dominant hypercytokinemia d ISGs are highly expressed in COVID-19 patients and exhibit pathogenic potential

An elevated level of viral diversity was found in some SARS-CoV-2 infected patients, indicating the risk of rapid evolution of the virus. Although no evidence for the transmission of intra-host variants was found, the risk should not be overlooked. Abstract:Background A novel coronavirus (SARS-CoV-2) has infected more than 75,000 individuals and spread to over 20 countries. It is still unclear how fast the virus evolved and how the virus interacts with other microorganisms in the lung. MethodsWe have conducted metatranscriptome sequencing for the bronchoalveolar lavage fluid of eight SARS-CoV-2 patients, 25 community-acquired pneumonia (CAP) patients, and 20 healthy controls. ResultsThe median number of intra-host variants was 1-4 in SARS-CoV-2 infected patients, which ranged between 0 and 51 in different samples. The distribution of variants on genes was similar to those observed in the population data (110 sequences).However, very few intra-host variants were observed in the population as polymorphism, implying either a bottleneck or purifying selection involved in the transmission of the virus, or a consequence of the limited diversity represented in the current polymorphism data. Although current evidence did not support the transmission of intra-host variants in a person-to-person spread, the risk should not be overlooked.The microbiota in SARS-CoV-2 infected patients was similar to those in CAP, either dominated by the pathogens or with elevated levels of oral and upper respiratory commensal bacteria.Conclusion SARS-CoV-2 evolves in vivo after infection, which may affect its virulence, infectivity, and transmissibility. Although how the intra-host variant spreads in the population is still elusive, it is necessary to strengthen the surveillance of the viral Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa203/5780800 by guest on 16 March 2020 4 evolution in the population and associated clinical changes.