Mucin 4 Protects Female Mice from Coronavirus Pathogenesis

Jessica A. Plante; Kenneth S. Plante; Lisa E. Gralinski; Anne Beall; Martin T. Ferris; Daniel Bottomly; Richard Green; Shannon K. McWeeney; Mark T. Heise; Ralph S. Baric; Vineet D. Menachery

and RNA expression analysis were leveraged to identify Muc4 as a high priority candidate gene 167 driving differences in SARS-CoV titer. Utilizing a Muc4 knockout mouse, a role was confirmed 168 for the gene in augmented SARS-CoV pathogenesis. While virus titers trended higher in Muc4 -/-169 mice at day 2 and 4, there was no statistically significant change as compared to WT control 170 mice. However, in absolute terms the Muc4 -/mice did have a modest 62% higher titer on day 171 two and a 51% higher titer on day four as compared to WT, and it is possible that this difference 172 is biologically significant despite the lack of statistical significance as determined by p-value 173 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.19.957118 doi: bioRxiv preprint (Lytsy et al., 2018; Vyas et al., 2015) . In addition, the loss of Muc4 was linked to enhanced 174 CHIKV disease in vivo. Together, this study highlights both the utility and the challenges in 175 transitioning from QTL hits to single-molecule studies. Our initial hypothesis for Muc4 to play a 176 role in controlling virus replication proved incorrect, or, at the very least, substantially more 177 complex than a simple, direct correlate; however, our exploration found a disease-interaction 178 that played a role in pathogenesis across multiple viruses. 179