Abstract
The novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic. Critical to the rapid evaluation of vaccines and antivirals against SARS-CoV-2 is the development of tractable animal models to understand the adaptive immune response to the virus. To this end, the use of common laboratory strains of mice is hindered by significant divergence of the angiotensin-converting enzyme 2 (ACE2), which is the receptor required for entry of SARS-CoV-2. In the current study, we designed and utilized an mRNA-based transfection system to induce expression of the hACE2 receptor in order to confer entry of SARS-CoV-2 in otherwise non-permissive cells. By employing this expression system in an in vivo setting, we were able to interrogate the adaptive immune response to SARS-CoV-2 in type 1 interferon receptor deficient mice. In doing so, we showed that the T cell response to SARS-CoV-2 is enhanced when hACE2 is expressed during infection. Moreover, we demonstrated that these responses are preserved in memory and are boosted upon secondary infection. Importantly, using this system, we functionally identified the CD4+ and CD8+ structural peptide epitopes targeted during SARS-CoV-2 infection in H2b restricted mice and confirmed their existence in an established model of SARS-CoV-2 pathogenesis. We demonstrated that, identical to what has been seen in humans, the antigen-specific CD8+ T cells in mice primarily target peptides of the spike and membrane proteins, while the antigen-specific CD4+ T cells target peptides of the nucleocapsid, membrane, and spike proteins. As the focus of the immune response in mice is highly similar to that of the humans, the identification of functional murine SARS-CoV-2-specific T cell epitopes provided in this study will be critical for evaluation of vaccine efficacy in murine models of SARS-CoV-2 infection.
Highlights
The pandemic level spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the resulting outbreak of coronavirus disease 2019 (COVID-19) drives a need for the development of a range of novel animal models to understand the virus induced pathology and evaluate vaccines and therapeutics
The development of tractable small animal models is critical to gain an understanding of the immune response to the novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and for the evaluation of vaccines against the virus
The development of murine models of infection has been hindered due to the lack of expression of the human angiotensin-converting enzyme 2, which is the receptor required for entry of SARS-CoV-2
Summary
The pandemic level spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the resulting outbreak of coronavirus disease 2019 (COVID-19) drives a need for the development of a range of novel animal models to understand the virus induced pathology and evaluate vaccines and therapeutics. Multiple studies have shown following the resolution of SARS-CoV-2 infection there is a strong neutralizing IgG antibody response detected against the receptor binding domain (RBD) of spike [5,6,7,8,9,10,11]. These studies support the development of vaccines that induce strong responses to the SARS-CoV-2 spike protein as they will induce T cell as well as antibody responses to the virus. What is currently needed are preclinical animal models, which can evaluate the efficacy and immunogenicity of the current vaccines as well as determine if the immune response generated against SARS-CoV-2 infection supports a protective or pathogenic role in COVID-19
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