SARS-CoV-2 infected human ACE2 transgenic pigs develop severe COVID-19-like pathology. (preprint)

COVID-19 continues to cause significant morbidity and mortality, with emerging strains rapidly spreading despite substantial immunity through vaccination and previous exposure. Animal models that accurately reflect COVID-19 are vital for testing mechanisms of disease, enabling development of improved vaccines and therapeutics. We have developed human ACE2 transgenic pigs that are highly susceptible to SARS-CoV-2 and display clinical signs, disease progression, and lung inflammation that faithfully replicate severe COVID-19 in humans.

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still adapting to its new human host. Attention has focussed on the viral spike protein, but substantial variation has been seen in the ORF8 gene. Here, we show that SARS-CoV-2 ORF8 protein undergoes signal peptide-mediated processing through the endoplasmic reticulum and is secreted as a glycosylated, disulphide-linked dimer. The secreted protein from the prototype SARS-CoV-2 virus had no major effect on viability of a variety of cell types, or on IFN or NF-{kappa}B signalling. However, it modulated cytokine expression from primary CSF1-derived human macrophages, most notably by decreasing IL-6 and IL-8 secretion. Furthermore, a sequence polymorphism L84S that appeared early in the pandemic associated with the Clade S lineage of virus, showed a markedly different effect, of increasing IL-6 production. We conclude that ORF8 sequence polymorphisms can potentially affect SARS-CoV-2 virulence and should therefore be monitored in sequencing-based surveillance.

Lack of evidence of ACE2 expression and replicative infection by SARS-CoV-2 in human endothelial cells (preprint)

A striking feature of severe COVID-19 is thrombosis in large as well as small vessels of multiple organs. This has led to the assumption that SARS-CoV-2 virus directly infects and damages the vascular endothelium. However, endothelial expression of ACE2, the cellular receptor for SARS-CoV-2, has not been convincingly demonstrated. Interrogating human bulk and single-cell transcriptomic data, we found ACE2 expression in endothelial cells to be extremely low or absent in vivo and not upregulated by exposure to inflammatory agents in vitro. Also, the endothelial chromatin landscape at the ACE2 locus showed presence of repressive and absence of activation marks, suggesting that the gene is inactive in endothelial cells. Finally, we failed to achieve infection and replication of SARS-CoV-2 in cultured human endothelial cells, which were permissive to productive infection by coronavirus 229E that uses CD13 as the receptor. Our data suggest that SARS-Cov-2 is unlikely to infect endothelial cells directly; these findings are consistent with a scenario where endothelial injury is indirectly caused by the infection of neighbouring epithelial cells and/or due to systemic effects mediated by immune cells, platelets, complement activation, and/or proinflammatory cytokines.

The Gender of COVID-19 Experts in Newspaper Articles: A Descriptive Cross-Sectional Study (preprint)

Background: Pre-existing gender-based disparities in academia may have worsened during the COVID-19 pandemic. There is anecdotal and peer-reviewed evidence that women in academia have been underrepresented in prestigious, pandemic-related opportunities. Being citated as an expert source in newspaper articles about COVID-19 may increase an individual's research or leadership profile. In addition, visibility in a newspaper article is an important component of representation in academia. Objective: We sought to determine whether women were underrepresented as COVID-19 expert sources in print newspapers in the United States. Design: We undertook a cross-sectional study of English-language newspaper articles that addressed the COVID-19 pandemic that were published in the top ten most widely read newspapers in the United States between Apr 1 and Apr 15, 2020. Main Measures: We extracted the names of all people cited as expert sources and categorized each expert sources as men, women, or another gender based on pronoun usage within the article or on a business, university, or organization website. Key Results: Of 2,297 expert sources identified, 35.9% (95% CI 33.9-37.8%; n=824) were women, 63.7% were men (95% CI 61.8-65.7%; n=1,464) and for 0.4%, gender could not be assigned (n=9). After removing duplicate experts, 1,738 unique individuals were cited, of which 34.6% were women (95% CI 32.3-36.8%; n=601), 64.9% were men (95% CI 62.7-67.1%; n=1,128), and 0.05% whose gender was unknown (n=9). Of articles with multiple experts referenced (n=374), 102 cited only men experts (27.3%) and 44 cited only women experts (11.8%).Conclusions: Altogether, this result supports that men are overrepresented compared to women as COVID-19 experts in newspaper articles.