SARS-CoV-2-Seronegative Subjects Target CTL Epitopes in the SARS-CoV-2 Nucleoprotein Cross-Reactive to Common Cold Coronaviruses

Abstract

The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.

Cellular interferon-gamma and interleukin-2 responses to SARS-CoV-2 structural proteins are broader and higher in those vaccinated after SARS-CoV-2 infection compared to vaccinees without prior SARS-CoV-2 infection

“…Longitudinal studies suggest that HCoVs induce a stable pool of memory CD4+ T cells that may account for the FluoroSpot IFN-γ responses in participants with no prior COVID-19 infection [ 63 ]. Cross-reactive epitopes present in SARS-CoV-2 and other HCoVs have been identified in the S, N and M proteins [ 46 , 61 , 64 – 66 ], including within the Sp6 and Mp1 subpools.…”

Selection and T-cell antigenicity of synthetic long peptides derived from SARS-CoV-2

“…Nethertheless, these data indicate that T-cell responses raised against these peptides may cross react with future SARS-CoV-2 variants, which may evolve to escape neutralising antibody responses, and against future emerging coronaviruses. This is supported by studies screening SARS-CoV-2 epitopes in COVID-19 and uninfected patients which have observed SARS-CoV-2 epitopes specific CD4+ and CD8+ T cell responses in SARS-CoV-2 uninfected individuals, which share homology with epitopes in other human coronaviruses [6, 8–10, 31]. The SARS-CoV-2 peptides studied here include 125 epitopes identified by these epitope screening studies of SARS-CoV-2 patients [6, 8, 9, 19, 31, 32].…”

“…This is supported by studies screening SARS-CoV-2 epitopes in COVID-19 and uninfected patients which have observed SARS-CoV-2 epitopes specific CD4+ and CD8+ T cell responses in SARS-CoV-2 uninfected individuals, which share homology with epitopes in other human coronaviruses [6, 8–10, 31]. The SARS-CoV-2 peptides studied here include 125 epitopes identified by these epitope screening studies of SARS-CoV-2 patients [6, 8, 9, 19, 31, 32]. A recent study, screening epitopes in 16 COVID-19 patients identified 122 epitopes reactive to T-cells in these individuals [33].…”

“…T-cell responses to SARS-CoV-1 demonstrate greater durability than those of neutralising antibody [5] and are associated with protection against SARS-CoV-2 [6], particularly in the context of waning antibody titres [7], indicating that T-cell mediated immunity may offer durable immune protection which may limit the severity of disease and potentially offer immune responses that are cross reactive to variant SARS-CoV-2 and other coronaviruses [6, 8, 9] similar to those have observed for different influenza viruses [10]. T-cell immune responses are generated by vaccination with the SARS-CoV-2 spike protein however these responses are thought to represent approximately 50% of the total anti-SARS-CoV-2 CD4+ T cell response and 25% of CD8+ T cell responses [11].…”

De novodesign of anti-variant COVID-19 Vaccine

“…Functional proteins were not considered since some of them are known to hijack MHC systems in human (25, 26, 27). There are numerous studies now for homology of nucleocapsid protein sequences between COVID and HuCoV strains (18, 28, 29, 30, 31). Also, T-cell response of COVID unexposed individuals to COVID was observed for at least one peptide from envelope protein (32) indicating potential effect from common cold immunity.…”