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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.
  • Swadling L; Division of Infection and Immunity, University College London, London, UK. l.swadling@ucl.ac.uk.
  • Diniz MO; Division of Infection and Immunity, University College London, London, UK.
  • Schmidt NM; Division of Infection and Immunity, University College London, London, UK.
  • Amin OE; Division of Infection and Immunity, University College London, London, UK.
  • Chandran A; Division of Infection and Immunity, University College London, London, UK.
  • Shaw E; Division of Infection and Immunity, University College London, London, UK.
  • Pade C; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Gibbons JM; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Le Bert N; Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.
  • Tan AT; Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.
  • Jeffery-Smith A; Division of Infection and Immunity, University College London, London, UK.
  • Tan CCS; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Tham CYL; UCL Genetics Institute, University College London, London, UK.
  • Kucykowicz S; Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.
  • Aidoo-Micah G; Division of Infection and Immunity, University College London, London, UK.
  • Rosenheim J; Division of Infection and Immunity, University College London, London, UK.
  • Davies J; Division of Infection and Immunity, University College London, London, UK.
  • Johnson M; Division of Infection and Immunity, University College London, London, UK.
  • Jensen MP; Great Ormond Street Institute of Child Health NIHR Biomedical Research Centre, University College London, London, UK.
  • Joy G; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • McCoy LE; Department of Cellular Pathology, Northwest London Pathology, Imperial College London NHS Trust, London, UK.
  • Valdes AM; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Chain BM; Institute of Cardiovascular Science, University College London, London, UK.
  • Goldblatt D; Division of Infection and Immunity, University College London, London, UK.
  • Altmann DM; Academic Rheumatology, Clinical Sciences, Nottingham City Hospital, Nottingham, UK.
  • Boyton RJ; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
  • Manisty C; Division of Infection and Immunity, University College London, London, UK.
  • Treibel TA; Great Ormond Street Institute of Child Health NIHR Biomedical Research Centre, University College London, London, UK.
  • Moon JC; Department of Immunology and Inflammation, Imperial College London, London, UK.
  • van Dorp L; Lung Division, Royal Brompton & Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • Balloux F; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • McKnight Á; Institute of Cardiovascular Science, University College London, London, UK.
  • Noursadeghi M; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
  • Bertoletti A; Institute of Cardiovascular Science, University College London, London, UK.
  • Maini MK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
Nature ; 601(7891): 110-117, 2022 01.
Article in English | MEDLINE | ID: covidwho-1510600
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: DNA-Directed RNA Polymerases / Asymptomatic Infections / Seroconversion / SARS-CoV-2 / COVID-19 Type of study: Etiology study / Incidence study / Observational study / Prognostic study / Randomized controlled trials / Risk factors Topics: Vaccines / Variants Limits: Female / Humans / Male Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-021-04186-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: DNA-Directed RNA Polymerases / Asymptomatic Infections / Seroconversion / SARS-CoV-2 / COVID-19 Type of study: Etiology study / Incidence study / Observational study / Prognostic study / Randomized controlled trials / Risk factors Topics: Vaccines / Variants Limits: Female / Humans / Male Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-021-04186-8