Outcome of SARS-CoV-2 reinfection depends on genetic background in female mice

Gagandeep Singh, Juan García-Bernalt Diego, Prajakta Warang, Seok-Chan Park, Lauren A. Chang, Moataz Noureddine, Gabriel Laghlali, Yonina Bykov, Matthew Prellberg, Vivian Yan, Sarabjot Singh, Lars Pache, Sara Cuadrado-Castano, Brett Webb, Adolfo García-Sastre and Michael Schotsaert ()
Additional contact information
Gagandeep Singh: Icahn School of Medicine at Mount Sinai New York
Juan García-Bernalt Diego: Icahn School of Medicine at Mount Sinai New York
Prajakta Warang: Icahn School of Medicine at Mount Sinai New York
Seok-Chan Park: Icahn School of Medicine at Mount Sinai New York
Lauren A. Chang: Icahn School of Medicine at Mount Sinai New York
Moataz Noureddine: Icahn School of Medicine at Mount Sinai New York
Gabriel Laghlali: Icahn School of Medicine at Mount Sinai New York
Yonina Bykov: Icahn School of Medicine at Mount Sinai New York
Matthew Prellberg: Icahn School of Medicine at Mount Sinai New York
Vivian Yan: Icahn School of Medicine at Mount Sinai New York
Sarabjot Singh: Civil Hospital
Lars Pache: Sanford-Burnham Prebys Medical Discovery Institute
Sara Cuadrado-Castano: Icahn School of Medicine at Mount Sinai New York
Brett Webb: University of Wyoming
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai New York
Michael Schotsaert: Icahn School of Medicine at Mount Sinai New York

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

Abstract: Abstract Antigenically distinct SARS-CoV-2 variants increase the reinfection risk for vaccinated and previously exposed population due to antibody neutralization escape. COVID-19 severity depends on many variables, including host immune responses, which differ depending on genetic predisposition. To address this, we perform immune profiling of female mice with different genetic backgrounds –transgenic K18-hACE2 and wild-type 129S1– infected with the severe B.1.351, 30 days after exposure to the milder BA.1 or severe H1N1. Prior BA.1 infection protects against B.1.351-induced morbidity in K18-hACE2 but aggravates disease in 129S1. H1N1 protects against B.1.351-induced morbidity only in 129S1. Enhanced severity in B.1.351 re-infected 129S1 is characterized by an increase of IL-10, IL-1β, IL-18 and IFN-γ, while in K18-hACE2 the cytokine profile resembles naïve mice undergoing their first viral infection. Enhanced pathology during 129S1 reinfection cannot be attributed to weaker adaptive immune responses to BA.1. Infection with BA.1 causes long-term differential remodeling and transcriptional changes in the bronchioalveolar CD11c+ compartment. K18-hACE2 CD11c+ cells show a strong antiviral defense expression profile whereas 129S1 CD11c+ cells present a more pro-inflammatory response upon restimulation. In conclusion, BA.1 induces cross-reactive adaptive immune responses in K18-hACE2 and 129S1, but reinfection outcome correlates with differential CD11c+ cells responses in the alveolar space.

Date: 2024
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DOI: 10.1038/s41467-024-54334-7

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