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Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 #MMPMID34758478
Swadling L; Diniz MO; Schmidt NM; Amin OE; Chandran A; Shaw E; Pade C; Gibbons JM; Le Bert N; Tan AT; Jeffery-Smith A; Tan CCS; Tham CYL; Kucykowicz S; Aidoo-Micah G; Rosenheim J; Davies J; Johnson M; Jensen MP; Joy G; McCoy LE; Valdes AM; Chain BM; Goldblatt D; Altmann DM; Boyton RJ; Manisty C; Treibel TA; Moon JC; van Dorp L; Balloux F; McKnight A; Noursadeghi M; Bertoletti A; Maini MK
Nature 2022[Jan]; 601 (7891): 110-117 PMID34758478show ga
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(1-3). Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. (4-11)), 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)(12,13), 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 IFI27, a robust early innate signature of SARS-CoV-2 (ref. (14)), 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 Coronaviridae.
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Nature 2022 ; 601 (7891): 110-117
