TY - JOUR
T1 - Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
AU - Swadling, Leo
AU - Diniz, Mariana O.
AU - Schmidt, Nathalie M.
AU - Amin, Oliver E.
AU - Chandran, Aneesh
AU - Shaw, Emily
AU - Pade, Corinna
AU - Gibbons, Joseph M.
AU - Le Bert, Nina
AU - Tan, Anthony T.
AU - Jeffery-Smith, Anna
AU - Tan, Cedric C. S.
AU - Tham, Christine Y. L.
AU - Kucykowicz, Stephanie
AU - Aidoo-Micah, Gloryanne
AU - Rosenheim, Joshua
AU - Davies, Jessica
AU - Johnson, Marina
AU - Jensen, Melanie P.
AU - Joy, George
AU - McCoy, Laura E.
AU - Valdes, Ana M.
AU - Chain, Benjamin M.
AU - Goldblatt, David
AU - Altmann, Daniel M.
AU - Boyton, Rosemary J.
AU - Manisty, Charlotte
AU - Treibel, Thomas A.
AU - Moon, James C.
AU - COVIDsortium Investigators
AU - van Dorp, Lucy
AU - Balloux, Francois
AU - McKnight, Áine
AU - Noursadeghi, Mahdad
AU - Bertoletti, Antonio
AU - Maini, Mala K.
A2 - Hickling, Lauren M.
N1 - Data availability statement: All data analysed during this study are included in this published article and its Supplementary Information. Genomic data analysed was obtained from the publicly available NCBI Virus database and, after registration, from the GISAID EpiCoV repository. The datasets generated during and/or analysed during the current study are available from the corresponding authors on reasonable request. Correspondence and requests for materials should be addressed to M.K.M. or L.S. Source data are provided with this paper.
Code availability statement: Custom scripts that were used to perform the homology searches, heatmap visualization and permutation testing are available at GitHub (https://github.com/cednotsed/tcell_cross_reactivity_covid.git).
PY - 2022/1/6
Y1 - 2022/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120703903&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04186-8
DO - 10.1038/s41586-021-04186-8
M3 - Article
SN - 0028-0836
VL - 601
SP - 110
EP - 117
JO - Nature
JF - Nature
IS - 7891
ER -