Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis. (preprint)

We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon (IFN) signaling pathway by directly interacting with Nup98-Rae1 at the nuclear pore complex (NPC) and disrupting bidirectional nucleo-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We show that ORF6 plays a key role in the antagonism of IFN signaling and in viral pathogenesis by interfering with karyopherin(importin)-mediated nuclear import during SARS-CoV-2 infection both in vitro, and in the Syrian golden hamster model in vivo. In addition, we found that ORF6-Nup98 interaction also contributes to inhibition of cellular mRNA export during SARS-CoV-2 infection. As a result, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Importantly, the now more abundant Omicron BA.5 lacks this loss-of-function polymorphism in ORF6. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2 and its evolving variants. ONE SENTENCE SUMMARYSARS-CoV-2 ORF6 subverts bidirectional nucleo-cytoplasmic trafficking to inhibit host gene expression and contribute to viral pathogenesis.

Pandemic-related decline in injuries related to women wearing high-heeled shoes: Analysis of U.S. data for 2016-2020 (preprint)

Background Wearing high-heeled shoes is associated with injury risk. During the COVID-19 pandemic, changes in work and social behavior may have reduced women’s use of such footwear. Methods This study assessed the trend in high-heel related injuries among U.S. women, using 2016-2020 data from the U.S. Consumer Product Safety Commission’s National Electronic Injury Surveillance System (NEISS). Results In 2020 there were an estimated 6,290 high-heel related emergency department visits involving women ages 15-69, down from 16,000 per year in 2016-2019. The 2020 decline began after the start of the COVID-19 shutdowns on March 15. There was no significant change in the percentage of fractures or hospital admissions. Conclusions The COVID-19 pandemic was associated with a decline in reported injuries related to high-heeled shoes among US women. If this resulted from fewer women wearing such shoes, and such habits influence future behavior, the result may be fewer injuries in the future.