Dataset Information

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

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.

SUBMITTER: Rosichini M

PROVIDER: S-EPMC9907790 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Rosichini Marco M Bordoni Veronica V Silvestris Domenico Alessandro DA Mariotti Davide D Matusali Giulia G Cardinale Antonella A Zambruno Giovanna G Condorelli Angelo Giuseppe AG Flamini Sara S Genah Shirley S Catanoso Marialuigia M Del Nonno Franca F Trezzi Matteo M Galletti Lorenzo L De Stefanis Cristiano C Cicolani Nicolò N Petrini Stefania S Quintarelli Concetta C Agrati Chiara C Locatelli Franco F Velardi Enrico E

The Journal of allergy and clinical immunology 20230208 4

<h4>Background</h4>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.<h4>Objective</h4 ...[more]

PMID: 36758836

Similar Datasets

Project description:Mounting evidence suggests that the gut-to-lung axis is critical during respiratory viral infections. We herein hypothesized that disruption of gut homeostasis during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may associate with early disease outcomes. To address this question, we took advantage of the Syrian hamster model. Our data confirmed that this model recapitulates some hallmark features of the human disease in the lungs. We further showed that SARS-CoV-2 infection associated with mild intestinal inflammation, relative alteration in intestinal barrier property and liver inflammation and altered lipid metabolism. These changes occurred concomitantly with an alteration of the gut microbiota composition over the course of infection, notably characterized by a higher relative abundance of deleterious bacterial taxa such as Enterobacteriaceae and Desulfovibrionaceae. Conversely, several members of the Ruminococcaceae and Lachnospiraceae families, including bacteria known to produce the fermentative products short-chain fatty acids (SCFAs), had a reduced relative proportion compared to non-infected controls. Accordingly, infection led to a transient decrease in systemic SCFA amounts. SCFA supplementation during infection had no effect on clinical and inflammatory parameters. Lastly, a strong correlation between some gut microbiota taxa and clinical and inflammation indices of SARS-CoV-2 infection severity was evidenced. Collectively, alteration of the gut microbiota correlates with disease severity in hamsters making this experimental model valuable for the design of interventional, gut microbiota-targeted, approaches for the control of COVID-19.Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; SCFAs, short-chain fatty acids; dpi, day post-infection; RT-PCR, reverse transcription polymerase chain reaction; IL, interleukin. ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2.

Project description:Measuring the adaptive immune response to SARS-CoV-2 can enable the assessment of past infection as well as protective immunity and the risk of reinfection. While neutralizing antibody (nAb) titers are one measure of protection, such assays are challenging to perform at a large scale and the longevity of the SARS-CoV-2 nAb response is not fully understood. Here, we apply a T-cell receptor (TCR) sequencing assay that can be performed on a small volume standard blood sample to assess the adaptive T-cell response to SARS-CoV-2 infection. Samples were collected from a cohort of 302 individuals recovered from COVID-19 up to 6 months after infection. Previously published findings in this cohort showed that two commercially available SARS-CoV-2 serologic assays correlate well with nAb testing. We demonstrate that the magnitude of the SARS-CoV-2-specific T-cell response strongly correlates with nAb titer, as well as clinical indicators of disease severity including hospitalization, fever, or difficulty breathing. While the depth and breadth of the T-cell response declines during convalescence, the T-cell signal remains well above background with high sensitivity up to at least 6 months following initial infection. Compared to serology tests detecting binding antibodies to SARS-CoV-2 spike and nucleoprotein, the overall sensitivity of the TCR-based assay across the entire cohort and all timepoints was approximately 5% greater for identifying prior SARS-CoV-2 infection. Notably, the improved performance of T-cell testing compared to serology was most apparent in recovered individuals who were not hospitalized and were sampled beyond 150 days of their initial illness, suggesting that antibody testing may have reduced sensitivity in individuals who experienced less severe COVID-19 illness and at later timepoints. Finally, T-cell testing was able to identify SARS-CoV-2 infection in 68% (55/81) of convalescent samples having nAb titers below the lower limit of detection, as well as 37% (13/35) of samples testing negative by all three antibody assays. These results demonstrate the utility of a TCR-based assay as a scalable, reliable measure of past SARS-CoV-2 infection across a spectrum of disease severity. Additionally, the TCR repertoire may be useful as a surrogate for protective immunity with additive clinical value beyond serologic or nAb testing methods.

Project description:BackgroundHost genetic factors may be associated with COVID-19 unfavourable outcomes. The first genome-wide association study (GWAS) conducted in individuals with respiratory failure due to COVID-19 revealed susceptibility loci close to six genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1) and the ABO blood-group gene. We aimed to investigate how polymorphisms in those genes could relate to lung function and severe asthma in a Brazilian population.MethodsDNA samples of 784 individuals following the ProAR (Programa para Controle da Asma e Rinite Alérgica da Bahia) were genotyped by the Multi-Ethnic Global Array panel with ∼2 million polymorphisms (Illumina). Polymorphisms in SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1 and the ABO blood-group gene were evaluated. Logistic regression for severe asthma, airway obstruction and lack of FEV1 reversibility was performed using PLINK software 1.9, in the additive model and was adjusted for sex, age and PCA-1. Pairwise Linkage disequilibrium analyses were performed using Haploview 4.2. The haplotypes and gene score analyses were performed in the SNPstat tool. In silico functions of polymorphisms were analysed using rSNPbase and RegulomeDB plataforms.ResultsWe identified the rs8176733 (G allele) and rs8176725 (A allele) in the ABO blood-group gene as risk factors for severe asthma, lower pulmonary obstruction and lack of FEV1 reversibility. Polymorphisms in CCR9 are risk factors for both severe asthma (A allele of rs34338823) and airway obstruction (A allele of rs6806802). The markers rs13079478 (A allele) and rs75817942 (A allele) in FYCO1 are related to more severe asthma and a lack of FEV1 reversibility, respectively. We identified the A allele of both rs35731912 and rs34338823 in LZTFL1 as risk factors for severe asthma. The marker rs6806802 (C allele) was associated with airway obstruction and rs7614952 (A allele), rs7625839 (G allele) and rs112509260 (A allele) are related to a lack of FEV1 reversibility. The A allele of rs2531747 in the SLC6A20 gene is also associated with severe asthma. Conversely, polymorphisms in XCR1 play a protective role in relation to severe asthma (A allele of rs2036295) and airway obstruction (A allele of rs2036295). Additionally, we found that individuals with a higher number of risk alleles have a greater risk of severe asthma, airway obstruction and FEV1 reversibility.ConclusionOur study suggests that polymorphisms in genes associated with respiratory failure in SARS-CoV-2-infected individuals are associated with greater susceptibility to severe asthma and reduced lung function in subjects with asthma.

Dataset Information

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

Background

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets