Human coronavirus OC43-elicited CD4+ T cells protect against SARS-CoV-2 in HLA transgenic mice

Rúbens Prince dos Santos Alves, Julia Timis, Robyn Miller, Kristen Valentine, Paolla Beatriz Almeida Pinto, Andrew Gonzalez, Jose Angel Regla-Nava, Erin Maule, Michael N. Nguyen, Norazizah Shafee, Sara Landeras-Bueno, Eduardo Olmedillas, Brett Laffey, Katarzyna Dobaczewska, Zbigniew Mikulski, Sara McArdle, Sarah R. Leist, Kenneth Kim, Ralph S. Baric, Erica Ollmann Saphire, Annie Elong Ngono () and Sujan Shresta ()
Additional contact information
Rúbens Prince dos Santos Alves: La Jolla Institute for Immunology
Julia Timis: La Jolla Institute for Immunology
Robyn Miller: La Jolla Institute for Immunology
Kristen Valentine: La Jolla Institute for Immunology
Paolla Beatriz Almeida Pinto: La Jolla Institute for Immunology
Andrew Gonzalez: La Jolla Institute for Immunology
Jose Angel Regla-Nava: La Jolla Institute for Immunology
Erin Maule: La Jolla Institute for Immunology
Michael N. Nguyen: La Jolla Institute for Immunology
Norazizah Shafee: La Jolla Institute for Immunology
Sara Landeras-Bueno: La Jolla Institute for Immunology
Eduardo Olmedillas: La Jolla Institute for Immunology
Brett Laffey: La Jolla Institute for Immunology
Katarzyna Dobaczewska: La Jolla Institute for Immunology
Zbigniew Mikulski: La Jolla Institute for Immunology
Sara McArdle: La Jolla Institute for Immunology
Sarah R. Leist: University of North Carolina at Chapel Hill
Kenneth Kim: La Jolla Institute for Immunology
Ralph S. Baric: University of North Carolina at Chapel Hill
Erica Ollmann Saphire: La Jolla Institute for Immunology
Annie Elong Ngono: La Jolla Institute for Immunology
Sujan Shresta: La Jolla Institute for Immunology

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract SARS-CoV-2-reactive T cells are detected in some healthy unexposed individuals. Human studies indicate these T cells could be elicited by the common cold coronavirus OC43. To directly test this assumption and define the role of OC43-elicited T cells that are cross-reactive with SARS-CoV-2, we develop a model of sequential infections with OC43 followed by SARS-CoV-2 in HLA-B*0702 and HLA-DRB1*0101 Ifnar1−/− transgenic mice. We find that OC43 infection can elicit polyfunctional CD8+ and CD4+ effector T cells that cross-react with SARS-CoV-2 peptides. Furthermore, pre-exposure to OC43 reduces subsequent SARS-CoV-2 infection and disease in the lung for a short-term in HLA-DRB1*0101 Ifnar1−/− transgenic mice, and a longer-term in HLA-B*0702 Ifnar1−/− transgenic mice. Depletion of CD4+ T cells in HLA-DRB1*0101 Ifnar1−/− transgenic mice with prior OC43 exposure results in increased viral burden in the lung but no change in virus-induced lung damage following infection with SARS-CoV-2 (versus CD4+ T cell-sufficient mice), demonstrating that the OC43-elicited SARS-CoV-2 cross-reactive T cell-mediated cross-protection against SARS-CoV-2 is partially dependent on CD4+ T cells. These findings contribute to our understanding of the origin of pre-existing SARS-CoV-2-reactive T cells and their effects on SARS-CoV-2 clinical outcomes, and also carry implications for development of broadly protective betacoronavirus vaccines.

Date: 2024
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DOI: 10.1038/s41467-024-45043-2

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