SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity - 05/04/23

Doi : 10.1016/j.jaci.2023.01.022

Marco Rosichini, MSc ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Veronica Bordoni, PhD ^a,^c,^{^{∗
These authors contributed equally to this work.}}, Domenico Alessandro Silvestris, PhD ^a, Davide Mariotti, MSc ^c, Giulia Matusali, PhD ^d, Antonella Cardinale, MSc ^a, Giovanna Zambruno, MD ^e, Angelo Giuseppe Condorelli, PhD ^e, Sara Flamini, PhD ^a, Shirley Genah, PhD ^a, Marialuigia Catanoso, MD ^a,^f, Franca Del Nonno, MD ^g, Matteo Trezzi, MD ^h, Lorenzo Galletti, MD ^h, Cristiano De Stefanis, MSc ⁱ, Nicolò Cicolani, BSc ^j, Stefania Petrini, PhD ^j, Concetta Quintarelli, PhD ^a,^k, Chiara Agrati, PhD ^a,^c,^{^{∗
These authors contributed equally to this work.}}, Franco Locatelli, MD ^a,^l,^{^{∗
These authors contributed equally to this work.}}, Enrico Velardi, PhD ^a,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
^e Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
^h Cardiac Surgery Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
ⁱ Pathology Unit, Core Research Laboratories, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
^j Confocal Microscopy Core Facility, Research Center, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
^b Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
^c Cellular Immunology Laboratory, INMI L Spallanzani – IRCCS, Rome, Italy
^d Virology Laboratory, INMI L Spallanzani – IRCCS, Rome, Italy
^g Pathology Unit, INMI L Spallanzani – IRCCS, Rome, Italy
^f Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
^k Department of Clinical Medicine and Surgery, University of Naples Federico II, Rome, Italy
^l Catholic University of the Sacred Heart, Rome, Italy

^∗Corresponding author: Enrico Velardi, PhD, Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, 00146, Italy.Department of Pediatric Hematology and OncologyCell and Gene TherapyBambino Gesù Children’s HospitalIRCCSRome00146Italy

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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.

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Graphical abstract

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Key words : COVID-19, SARS-CoV-2, immunodeficiency, thymus, T cells, thymic epithelial cells

Abbreviations used : ACE2, βTREC, cjKREC, CK1, CK5, COVID-19, cTEC, DEGs, EpCAM, hTEC, ICU, KREC, LCMV, mTEC, sjKREC, sjTREC, TEC, SARS-CoV-2, TREC, UEA1

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Methods

Study design

Generation of hTEC cultures

SARS-CoV-2 infection of TECs

Viral RNA quantification

Immunofluorescence

RNA-sequencing and bioinformatics analysis

Flow cytometry and cell sorting

TREC and KREC quantification

Statistics

Results

T- and B-cell neogenesis is impaired in patients with COVID-19

In vivo SARS-CoV-2 infection of TECs

In vitro SARS-CoV-2 infection of primary human TECs

SARS-CoV-2 infection affects gene expression in primary human TECs

Discussion

E.V. was supported by grants from the Amy Stelzer Manasevit Research Program, the Italian Association for Cancer Research (AIRC), and the Italian Ministry of Health (“Ricerca Corrente”). F.L. was supported by grants from AIRC (Special Program Metastatic disease: The Key Unmet Need in Oncology 5 per mille 2018 Project Code 21147 and Accelerator Award 2017 INCAR), Ministero dell’Istruzione dell’Università e della Ricerca (grant PRIN ID 2017 WC8499_004), and the Italian Ministry of Health (grant RF-2016-02364388). S.F and S.G. were supported by the AIRC fellowship for Italy. The study was also supported by the European Virus Archive - GLOBAL funded by European Union's Horizon 2020 research and innovation programme (grant agreement no. 871029).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 151 - N° 4

P. 911-921 - Aprile 2023 Ritorno al numero

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SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity - 05/04/23

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Graphical abstract

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