SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity

• DOI: 10.1016/j.jaci.2023.01.022
• Publication Date: 2023-02-08T23:17:29Z
• Authors: Marco Rosichini; Veronica Bordoni; Domenico Alessand...; Davide Mariotti; Giulia Matusali; Antonella Cardinale; Giovanna Zambruno; Angelo Giuseppe C...; Sara Flamini; Shirley Genah; Marialuigia Catanoso; Franca Del Nonno; Matteo Trezzi; Lorenzo Galletti; Cristiano De Stef...; Nicolò Cicolani; Stefania Petrini; Concetta Quintarelli; Chiara Agrati; Franco Locatelli; Enrico Velardi
• Keywords: 0301 basic medicine; SARS-CoV-2; T cells; Patient Acuity; T cell; 610; COVID-19; Thymus Gland; 3. Good health; 03 medical and health sciences; thymus; thymic epithelial cells; Lymphopenia; 616; COVID-19; SARS-CoV-2; T cells; immunodeficiency; thymic epithelial cells; thymus; Humans; thymic epithelial cell; Covid-19; immunodeficiency

Lymphopenia, particularly when restricted to the T-cell compartment, has been described as one of the major clinical hallmarks in patients with coronavirus disease 2019 (COVID-19) and proposed as an indicator of disease severity. Although several mechanisms fostering COVID-19-related lymphopenia have been described, including cell apoptosis and tissue homing, the underlying causes of the decline in T-cell count and function are still not completely understood.Given that viral infections can directly target thymic microenvironment and impair the process of T-cell generation, we sought to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on thymic function.We performed molecular quantification of T-cell receptor excision circles and κ-deleting recombination excision circles to assess, respectively, T- and B-cell neogenesis in SARS-CoV-2-infected patients. We developed a system for in vitro culture of primary human thymic epithelial cells (TECs) to mechanistically investigate the impact of SARS-CoV-2 on TEC function.We showed that patients with COVID-19 had reduced thymic function that was inversely associated with the severity of the disease. We found that angiotensin-converting enzyme 2, through which SARS-CoV-2 enters the host cells, was expressed by thymic epithelium, and in particular by medullary TECs. We also demonstrated that SARS-CoV-2 can target TECs and downregulate critical genes and pathways associated with epithelial cell adhesion and survival.Our data demonstrate that the human thymus is a target of SARS-CoV-2 and thymic function is altered following infection. These findings expand our current knowledge of the effects of SARS-CoV-2 infection on T-cell homeostasis and suggest that monitoring thymic activity may be a useful marker to predict disease severity and progression.