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

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; Altmann, Daniel M.; Boyton, Rosemary J.; Manisty, Charlotte; Treibel, Thomas A.; Moon, James C.; van Dorp, Lucy; Balloux, Francois; McKnight, Áine; Noursadeghi, Mahdad; Bertoletti, Antonio; Maini, Mala K.; Investigators, COVIDsortium

Abstract

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24–11, 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 (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, 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 (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. 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.

Citation

Swadling, L., Diniz, M. O., Schmidt, N. M., Amin, O. E., Chandran, A., Shaw, E., Pade, C., Gibbons, J. M., Le Bert, N., Tan, A. T., Jeffery-Smith, A., Tan, C. C. S., Tham, C. Y. L., Kucykowicz, S., Aidoo-Micah, G., Rosenheim, J., Davies, J., Johnson, M., Jensen, M. P., Joy, G., …Investigators, C. (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

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2021
• Online Publication Date: Nov 10, 2021
• Publication Date: Jan 6, 2022
• Deposit Date: Jan 30, 2022
• Publicly Available Date: Feb 1, 2022
• Journal: Nature
• Print ISSN: 0028-0836
• Electronic ISSN: 1476-4687
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 601
• Issue: 7891
• Pages: 110-117
• DOI: https://doi.org/10.1038/s41586-021-04186-8
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/7354449
• Publisher URL: https://www.nature.com/articles/s41586-021-04186-8
• Additional Information: COVIDsortium Investigators; Hakam Abbass, Aderonke Abiodun, Mashael Alfarih, Zoe Alldis, Daniel M. Altmann, Oliver E. Amin, Mervyn Andiapen, Jessica Artico, João B. Augusto, Georgina L. Baca, Sasha N. L. Bailey, Anish N. Bhuva, Alex Boulter, Ruth Bowles, Rosemary J. Boyton, Olivia V. Bracken, Ben O’Brien, Tim Brooks, Natalie Bullock, David K. Butler, Gabriella Captur, Nicola Champion, Carmen Chan, Aneesh Chandran, David Collier, Jorge Couto de Sousa, Xose Couto-Parada, Teresa Cutino-Mogue, Rhodri H. Davies, Brooke Douglas, Cecilia Di Genova, Keenan Dieobi-Anene, Mariana O. Diniz, Anaya Ellis, Karen Feehan, Malcolm Finlay, Marianna Fontana, Nasim Forooghi, Celia Gaier, Joseph M. Gibbons, Derek Gilroy, Matt Hamblin, Gabrielle Harker, Jacqueline Hewson, Lauren M. Hickling, Aroon D. Hingorani, Lee Howes, Alun Hughes, Gemma Hughes, Rebecca Hughes, Ivie Itua, Victor Jardim, Wing-Yiu Jason Lee, Melanie Petra Jensen, Jessica Jones, Meleri Jones, George Joy, Vikas Kapil, Hibba Kurdi, Jonathan Lambourne, Kai-Min Lin, Sarah Louth, Mala K. Maini, Vineela Mandadapu, Charlotte Manisty, Áine McKnight, Katia Menacho, Celina Mfuko, Oliver Mitchelmore, Christopher Moon, James C. Moon, Diana Munoz-Sandoval, Sam M. Murray, Mahdad Noursadeghi, Ashley Otter, Corinna Pade, Susana Palma, Ruth Parker, Kush Patel, Babita Pawarova, Steffen E. Petersen, Brian Piniera, Franziska P. Pieper, Daniel Pope, Mary Prossora, Lisa Rannigan, Alicja Rapala, Catherine J. Reynolds, Amy Richards, Matthew Robathan, Joshua Rosenheim, Genine Sambile, Nathalie M. Schmidt, Amanda Semper, Andreas Seraphim, Mihaela Simion, Angelique Smit, Michelle Sugimoto, Leo Swadling, Stephen Taylor, Nigel Temperton, Stephen Thomas, George D. Thornton, Thomas A. Treibel, Art Tucker, Jessry Veerapen, Mohit Vijayakumar, Sophie Welch, Theresa Wodehouse, Lucinda Wynne & Dan Zahedi.