Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

Sims, Amy C.; Schäfer, Alexandra; Okuda, Kenichi; Leist, Sarah R.; Kocher, Jacob F.; Cockrell, Adam S.; Hawkins, Padraig E.; Furusho, Minako; Jensen, Kara L.; Kyle, Jennifer E.; Burnum-Johnson, Kristin E.; Stratton, Kelly G.; Lamar, Natalie C.; Niccora, Carrie D.; Weitz, Karl K.; Smith, Richard D.; Metz, Thomas O.; Waters, Katrina M.; Boucher, Richard C.; Montgomery, Stephanie A.; Baric, Ralph S.; Sheahan, Timothy P.

doi:10.1128/msphere.00951-24

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

Journal Article · Thu Jan 30 00:00:00 EST 2025 · mSphere

DOI:https://doi.org/10.1128/msphere.00951-24· OSTI ID:2581056

Sims, Amy C. ^[1]; Schäfer, Alexandra ^[1]; Okuda, Kenichi ^[1]; Leist, Sarah R. ^[1]; Kocher, Jacob F. ^[1]; Cockrell, Adam S. ^[1]; Hawkins, Padraig E. ^[1]; Furusho, Minako ^[1]; Jensen, Kara L. ^[1]; Kyle, Jennifer E. ^[2]; ^[2]; ^[2]; ^[2]; ^[2]; ^[2]; Smith, Richard D. ^[2]; ^[2]; ^[2]; Boucher, Richard C. ^[1]; Montgomery, Stephanie A. ^[1] more »

University of North Carolina, Chapel Hill, NC (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2581056

Report Number(s):: PNNL-SA--204428

Journal Information:: mSphere, Journal Name: mSphere Journal Issue: 2 Vol. 10; ISSN 2379-5042

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

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