SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

Nature

Abstract

Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to ‘common cold’ human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.

Main

SARS-CoV-2 is the cause of COVID-19. This disease has been declared a pandemic by the World Health Organization (WHO), and is having severe effects on both individual lives and economies around the world. Infection with SARS-CoV-2 is characterized by a broad spectrum of clinical syndromes, which range from asymptomatic disease or mild influenza-like symptoms to severe pneumonia and acute respiratory distress syndrome.

It is common to observe the ability of a single virus to cause widely differing pathological manifestations in humans. This is often due to multiple contributing factors including the size of the viral inoculum, the genetic background of patients and the presence of concomitant pathological conditions. Moreover, an established adaptive immunity towards closely related viruses or other microorganisms can reduce susceptibility or enhance disease severity.

SARS-CoV-2 belongs to the Coronaviridae, a family of large RNA viruses that infect many animal species. Six other coronaviruses are known to infect humans. Four of them are endemically transmitted and cause the common cold (OC43, HKU1, 229E and NL63), while SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) have caused epidemics of severe pneumonia. All of these coronaviruses trigger antibody and T cell responses in infected patients: however, antibody levels appear to wane faster than T cells. SARS-CoV-specific antibodies dropped below the limit of detection within 2 to 3 years, whereas SARS-CoV-specific memory T cells have been detected even 11 years after SARS. As the sequences of selected structural and non-structural proteins are highly conserved among different coronaviruses (for example, NSP7 and NSP13 are 100% and 99% identical, respectively, between SARS-CoV-2, SARS-CoV and the bat-associated bat-SL-CoVZXC21), we investigated whether cross-reactive SARS-CoV-2-specific T cells are present in individuals who resolved SARS-CoV, and compared the responses with those present in individuals who recovered from SARS-CoV-2 infection. We also studied these T cells in individuals with no history of SARS or COVID-19 or of contact with patients with SARS-CoV-2. Collectively these individuals are hereafter referred to as individuals who were not exposed to SARS-CoV and SARS-CoV-2 (unexposed donors).

SARS-CoV-2-specific T cells in patients with COVID-19

SARS-CoV-2-specific T cells have just started to be characterized for patients with COVID-19 and their potential protective role has been inferred from studies of patients who recovered from SARS and MERS. To study SARS-CoV-2-specific T cells associated with viral clearance, we collected peripheral blood from 36 individuals after recovery from mild to severe COVID-19 (demographic, clinical and virological information is included in Extended Data Table 1) and studied the T cell response against selected structural (N) and non-structural proteins (NSP7 and NSP13 of ORF1) of the large SARS-CoV-2 proteome (Fig. 1a). We selected the N protein as it is one of the more-abundant structural proteins produced17 and has a high degree of homology between different betacoranaviruses18 (Extended Data Fig. 1).

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Source: Springer Nature

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