Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.
Diniz, Mariana O
Amin, Oliver E
Tan, Anthony T
Tan, Cedric CS
Jensen, Melanie P
Altmann, Daniel M
Treibel, Thomas A
Moon, James C
Springer Science and Business Media LLC
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Swadling, L., Diniz, M. O., Schmidt, N. M., Amin, O. E., Chandran, A., Shaw, E., Pade, C., et al. (2022). Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.. Nature, 601 (7891), 110-117. https://doi.org/10.1038/s41586-021-04186-8
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.
Article, /631/250/2152/1566/1571, /631/250/254, /631/250/1619/554, /631/326/596/4130, /13/1, /13/31, /13/106, /82/75, article
External DOI: https://doi.org/10.1038/s41586-021-04186-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333055