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Eser, Tabea M.; Baranov, Olga; Huth, Manuel; Ahmed, Mohammed I. M.; Deák, Flora; Held, Kathrin; Lin, Luming; Pekayvaz, Kami; Leunig, Alexander; Nicolai, Leo; Pollakis, Georgios; Buggert, Marcus; Price, David A.; Rubio-Acero, Raquel; Reich, Jakob; Falk, Philine; Markgraf, Alissa; Puchinger, Kerstin; Castelletti, Noemi; Olbrich, Laura; Vanshylla, Kanika; Klein, Florian; Wieser, Andreas; Hasenauer, Jan; Kroidl, Inge; Hoelscher, Michael; Geldmacher, Christof (2023): Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion. Nature Communications, 14 (1). ISSN 2041-1723

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Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4+ and CD8+ T cells correlate inversely with various inflammatory markers and UA-VLs. In addition, we show that high frequencies of activated CD4+ and CD8+ T cells are present in acutely infected nasopharyngeal tissue, many of which express genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of IFNG mRNA-expressing CD4+ and CD8+ T cells in the infected epithelium is further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identify an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19.

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