Sophie-Marie Aicher, University of Toronto

Sophie-Marie Aicher1,2, Celine Tan1,3, Max Erdmann4, Leandro Xavier-Neves4, Levi Klassen3, Briallen Lobb5, Shyan Mascarenhas5, Jonathon D Kotwa3, Yaejin Lee1,3, Sowmya Thanikachalam6, Lauren Crawshaw7, Theo J Moraes6, Jeff Bowman7, Edward Emmott4, Andrew C Doxey5, Arinjay Banerjee1,2, Samira Mubareka1,3 1Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada 2Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada 3Sunnybrook Research Institute, Toronto, ON, Canada 4Department of Biochemistry, Cell and Systems Biology, University of Liverpool, Liverpool, Merseyside, Great Britain 5Department of Biology, University of Waterloo, Waterloo, ON, Canada 6The Hospital for Sick Children, Peter Gilgan Center for Research and Learning, Toronto, ON, Canada 7Wildlife Research and Monitoring Section, Ontario Ministry of Natural Resources, Peterborough, ON, Canada

Fighting & Responding

Zoonotic viruses, including SARS-CoV-2, have increasingly caused public health emergencies. While often non-pathogenic in reservoir species, knowledge concerning protective features in wildlife reservoirs remains sparse. SARS-CoV-2 circulates subclinically among white-tailed deer (WTD) populations, and we isolated the divergent strain, B.1.641, from WTD with evidence of deer-to-human spillback. Little is known about WTD responses to SARS-CoV-2 or the factors influencing lack of clinical disease. Here, we characterize SARS-CoV-2 infection and perform mechanistic studies in novel WTD cellular systems. We performed RNA-seq on samples from naturally infected WTD, and observed strong upregulation of immune genes like ISG15 and MX1. Next, we generated ciliated nasal epithelia on air-liquid interface from WTD nasal brushes, and investigated viral replication and infection-induced cellular responses to SARS-CoV-2 B.1.641 and Delta variants using bulk transcriptomics. Our results highlight strong upregulation of type I and III interferons and associated antiviral genes like MX1 and BST2. Importantly, SARS-CoV-2 Delta only moderately induced antiviral genes in WTD cells but genes associated with remodeling of extracellular matrix and inhibition of cilium assembly were significantly upregulated. We confirmed the transcriptional upregulation of multiple genes like MX2 and IFIT1 at the protein level using label‑free quantitative proteomics. Together, our data highlight the existence of potent antiviral immune responses in WTD upon SARS-CoV-2 infection. Our novel WTD cells are useful tools to investigate the interplay between SARS-CoV-2 variants and a potential novel reservoir host. Characterization of viral tolerance in reservoir species will further decipher zoonotic spillovers and pinpoint targets for therapeutic intervention against emerging viruses.