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

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.

Long COVID: Long-Term Impact of SARS-CoV2

“…Prolonged infections of mouse models with SARS-CoV-2 for an extended period may also provide valuable insights into LC development. Just recently, Dos Santos Alves and colleagues showed that human coronavirus OC43-elicited CD4+ T cells are protective against SARS-CoV-2 in HLA transgenic mice [72]. This validates that SARS-CoV-2-reactive T cells are detected in some healthy, unexposed individuals, just as other human studies indicate these T cells could be elicited by the common cold coronavirus OC43.…”

Protective interplay: Mycobacterium tuberculosis diminishes SARS-CoV-2 severity through innate immune priming

“…An early, and Th1-leaning CD4+ T cell response is deemed important for combatting SARS-CoV-2 ( 59 ). Additionally, a study has shown that pre-existing CD4+ T cells induced from previous infection provided protection against SARS-CoV-2 ( 60 ). Similarly, IFNγ has demonstrated driving vaccine-induced cellular immunity in K18-hACE2 transgenic B-cell deficient (μMT) mice ( 61 ) and recently confirmed to induce early control of SARS-CoV-2 infection when administered intranasally to wildtype C57BL/6 mice ( 62 ).…”

Harnessing T-Cells for Enhanced Vaccine Development against Viral Infections

“…Studies have revealed that pre-existing CD4 + T-cells in humans respond to pandemic 2009 H1N1 peptides, correlating with reduced virus shedding and milder illness during IAV infection [10]. Additionally, research confirms the existence of protective cross-reactive T-cell responses among human coronaviruses [11][12][13], mirroring the diverse protective effects of cross-reactive T-cells against the influenza virus (IV) [14,15]. Notably, specific memory T-cell populations boast an extended lifespan, with highly conserved T-cell epitopes, rendering viruses more prone to evading humoral immunity over T-cell immunity [16][17][18][19][20][21].…”