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Swadling, Leo; Diniz, Mariana O.; Schmidt, Nathalie M.; Amin, Oliver E.; Chandran, Aneesh; Shaw, Emily; Pade, Corinna; Gibbons, Joseph M.; Le Bert, Nina; Tan, Anthony T.; Jeffery-Smith, Anna; Tan, Cedric C. S.; Tham, Christine Y. L.; Kucykowicz, Stephanie; Aidoo-Micah, Gloryanne; Rosenheim, Joshua; Davies, Jessica; Johnson, Marina; Jensen, Melanie P.; Joy, George; McCoy, Laura E.; Valdes, Ana M.; Chain, Benjamin M.; Goldblatt, David; [...]

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

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  • Media type: E-Article
  • Title: Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
  • Contributor: Swadling, Leo; Diniz, Mariana O.; Schmidt, Nathalie M.; Amin, Oliver E.; Chandran, Aneesh; Shaw, Emily; Pade, Corinna; Gibbons, Joseph M.; Le Bert, Nina; Tan, Anthony T.; Jeffery-Smith, Anna; Tan, Cedric C. S.; Tham, Christine Y. L.; Kucykowicz, Stephanie; Aidoo-Micah, Gloryanne; Rosenheim, Joshua; Davies, Jessica; Johnson, Marina; Jensen, Melanie P.; Joy, George; McCoy, Laura E.; Valdes, Ana M.; Chain, Benjamin M.; Goldblatt, David; [...]
  • imprint: Springer Science and Business Media LLC, 2022
  • Published in: Nature
  • Language: English
  • DOI: 10.1038/s41586-021-04186-8
  • ISSN: 0028-0836; 1476-4687
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections<jats:sup>1–3</jats:sup>. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. <jats:sup>4–11</jats:sup>), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)<jats:sup>12,13</jats:sup>, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in <jats:italic>IFI27</jats:italic>, a robust early innate signature of SARS-CoV-2 (ref. <jats:sup>14</jats:sup>), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging <jats:italic>Coronaviridae</jats:italic>.</jats:p>