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.

Rosichini, M., Bordoni, V., Silvestris, D. A., Mariotti, D., Matusali, G., Cardinale, A., Zambruno, G., Condorelli, A. G., Flamini, S., Genah, S., Catanoso, M., Del Nonno, F., Trezzi, M., Galletti, L., De Stefanis, C., Cicolani, N., Petrini, S., Quintarelli, C., Agrati, C., Locatelli, F., Velardi, E., SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity, <<JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY>>, 2023; (151): 911-921. [doi:10.1016/j.jaci.2023.01.022] [https://hdl.handle.net/10807/236171]

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

Locatelli, Franco
Penultimo
Writing – Review & Editing
;
2023

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.
2023
Inglese
Rosichini, M., Bordoni, V., Silvestris, D. A., Mariotti, D., Matusali, G., Cardinale, A., Zambruno, G., Condorelli, A. G., Flamini, S., Genah, S., Catanoso, M., Del Nonno, F., Trezzi, M., Galletti, L., De Stefanis, C., Cicolani, N., Petrini, S., Quintarelli, C., Agrati, C., Locatelli, F., Velardi, E., SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity, <<JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY>>, 2023; (151): 911-921. [doi:10.1016/j.jaci.2023.01.022] [https://hdl.handle.net/10807/236171]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/236171
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