Genetic signature detected in T cell receptors from patients with severe COVID-19

Manuel Corpas; Carmen de Mendoza; Víctor Moreno-Torres; Ilduara Pintos; Pedro Seoane; James R Perkins; Juan A G Ranea; Segun Fatumo; Tamas Korcsmaros; José Manuel Martín-Villa; Pablo Barreiro; Octavio Corral; Vicente Soriano

doi:10.1016/j.isci.2023.107735

Genetic signature detected in T cell receptors from patients with severe COVID-19

iScience. 2023 Aug 25;26(10):107735. doi: 10.1016/j.isci.2023.107735. eCollection 2023 Oct 20.

Authors

Manuel Corpas^{1

2

3

4}, Carmen de Mendoza⁵, Víctor Moreno-Torres^{3

5}, Ilduara Pintos⁵, Pedro Seoane^{6

7}, James R Perkins^{6

7

8}, Juan A G Ranea^{6

7

8

9}, Segun Fatumo^{10

11

12}, Tamas Korcsmaros¹³, José Manuel Martín-Villa¹⁴, Pablo Barreiro^{3

15}, Octavio Corral³, Vicente Soriano³

Affiliations

¹ School of Life Sciences, University of Westminster, London, UK.
² Cambridge Precision Medicine Limited, ideaSpace, University of Cambridge Biomedical Innovation Hub, Cambridge, UK.
³ UNIR Health Sciences School & Medical Center, Madrid, Spain.
⁴ Institute of Continuing Education, University of Cambridge, Cambridge, UK.
⁵ Puerta de Hierro University Hospital & Research Institute, Majadahonda, Spain.
⁶ Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain.
⁷ CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁸ The Biomedical Research Institute of Málaga (IBIMA), Málaga, Spain.
⁹ Spanish National Bioinformatics Institute (INB/ELIXIR-ES), Madrid, Spain.
¹⁰ The African Computational Genomics (TACG) Research Group, MRC/UVRI and LSHTM, Entebbe, Uganda.
¹¹ London School of Hygiene and Tropical Medicine, London, UK.
¹² H3Africa Bioinformatics Network (H3ABioNet) Node, Centre for Genomics Research and Innovation, NABDA/FMST, Abuja, Nigeria.
¹³ Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
¹⁴ Department of Immunology, Complutense University and IIS Gregorio Marañón, Madrid, Spain.
¹⁵ Emergency Hospital Isabel Zendal, Madrid, Spain.

Abstract

Characterization of host genetic factors contributing to COVID-19 severity promises advances on drug discovery to fight the disease. Most genetic analyses to date have identified genome-wide significant associations involving loss-of-function variants for immune response pathways. Despite accumulating evidence supporting a role for T cells in COVID-19 severity, no definitive genetic markers have been found to support an involvement of T cell responses. We analyzed 205 whole exomes from both a well-characterized cohort of hospitalized severe COVID-19 patients and controls. Significantly enriched high impact alleles were found for 25 variants within the T cell receptor beta (TRB) locus on chromosome 7. Although most of these alleles were found in heterozygosis, at least three or more in TRBV6-5, TRBV7-3, TRBV7-6, TRBV7-7, and TRBV10-1 suggested a possible TRB loss of function via compound heterozygosis. This loss-of-function in TRB genes supports suboptimal or dysfunctional T cell responses as a major contributor to severe COVID-19 pathogenesis.

Keywords: Genetics; Genomics; Immunology; Virology.