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

Marco Rosichini; Veronica Bordoni; Domenico Alessandro Silvestris; Davide Mariotti; Giulia Matusali; Antonella Cardinale; Giovanna Zambruno; Angelo Giuseppe Condorelli; Sara Flamini; Shirley Genah; Marialuigia Catanoso; Franca Del Nonno; Matteo Trezzi; Lorenzo Galletti; Cristiano De Stefanis; Nicolò Cicolani; Stefania Petrini; Concetta Quintarelli; Chiara Agrati; Franco Locatelli; Enrico Velardi

doi:10.1016/j.jaci.2023.01.022

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

J Allergy Clin Immunol. 2023 Apr;151(4):911-921. doi: 10.1016/j.jaci.2023.01.022. Epub 2023 Feb 8.

Authors

Marco Rosichini¹, Veronica Bordoni², Domenico Alessandro Silvestris³, Davide Mariotti⁴, Giulia Matusali⁵, Antonella Cardinale³, Giovanna Zambruno⁶, Angelo Giuseppe Condorelli⁶, Sara Flamini³, Shirley Genah³, Marialuigia Catanoso⁷, Franca Del Nonno⁸, Matteo Trezzi⁹, Lorenzo Galletti⁹, Cristiano De Stefanis¹⁰, Nicolò Cicolani¹¹, Stefania Petrini¹¹, Concetta Quintarelli¹², Chiara Agrati², Franco Locatelli¹³, Enrico Velardi¹⁴

Affiliations

¹ Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
² Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Cellular Immunology Laboratory, INMI L Spallanzani - IRCCS, Rome, Italy.
³ Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴ Cellular Immunology Laboratory, INMI L Spallanzani - IRCCS, Rome, Italy.
⁵ Virology Laboratory, INMI L Spallanzani - IRCCS, Rome, Italy.
⁶ Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁷ Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
⁸ Pathology Unit, INMI L Spallanzani - IRCCS, Rome, Italy.
⁹ Cardiac Surgery Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁰ Pathology Unit, Core Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹¹ Confocal Microscopy Core Facility, Research Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Rome, Italy.
¹³ Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy.
¹⁴ Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: [email protected].

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: COVID-19; SARS-CoV-2; T cells; immunodeficiency; thymic epithelial cells; thymus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19* / metabolism
Humans
Lymphopenia* / genetics
Patient Acuity
SARS-CoV-2
Thymus Gland