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

Published version
Peer-reviewed

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Authors

Diniz, Mariana O 
Schmidt, Nathalie M  ORCID logo  https://orcid.org/0000-0002-9841-8418
Amin, Oliver E 
Chandran, Aneesh 

Abstract

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 infections1-3. 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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Keywords

Asymptomatic Infections, COVID-19, Cell Proliferation, Cohort Studies, DNA-Directed RNA Polymerases, Evolution, Molecular, Female, Health Personnel, Humans, Male, Membrane Proteins, Memory T Cells, Multienzyme Complexes, SARS-CoV-2, Seroconversion, Transcription, Genetic

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

601

Publisher

Springer Science and Business Media LLC