Lymphopenia: The thymus is a target of SARS-CoV-2

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A new study by Italian researchers has found that the SARS-CoV-2 virus is able to infect the thymus and impair T cell generation that can lead to disease severity.

The study findings were published in the peer reviewed Journal of Allergy and Clinical Immunology.
https://www.sciencedirect.com/science/article/pii/S0091674923001471

Since its emergence in December 2019, SARS-CoV-2 has quickly spread across the globe. The virus exploits ACE2 as the primary cell entry receptor, and its infection leads to the highly infective COVID-19. Given the complexity of the disease and the surge of viral variants with high fatality risk, it is paramount to comprehensively characterize the effects of the virus on its biologic targets to develop effective treatments against COVID-19 and identify patients at risk of severe disease.

Clinically, COVID-19 is associated with a broad spectrum of symptoms and complications. Although a large body of literature has investigated the effects of the infection on lymphopenia, very few studies have assessed whether the process of T-cell and B-cell lymphopoiesis is altered in patients with COVID-19.

Here we present for the first time evidence that the thymus is a target of SARS-CoV-2 infection in vivo and that thymic function is impaired in patients with COVID-19. We first demonstrated that patients with COVID-19 display decreased levels of TRECs and KRECs, which represent surrogate markers of T- and B-cell neogenesis, respectively.

Moreover, our data demonstrated a more severe reduction in TREC levels in both non-ICU and ICU patients, whereas KRECs were less affected. These results are in agreement with previously published data showing that the T-cell pool is more affected during COVID-19 than the B-cell compartment is.46,54 Given these results, we sought to investigate a possible direct impact of SARS-CoV-2 on the thymus.

Our data demonstrated that thymic epithelium of pediatric and adult patients expresses the SARS-CoV-2 receptor ACE2 and that SARS-CoV-2 entry into the cells resulted in fundamental changes in gene expression profile. Our data suggest that following infection, SARS-CoV-2 recruits a variety of host factors to survive and propagate itself, as suggested by the activation of different pathways associated with ribosome biogenesis and protein translation.

These effects are associated with the derangement of the normal gene expression profile in TECs, leading to the downregulation of crucial pathways involved in epithelium cell maintenance (such as focal adhesion and extracellular matrix interaction) and upregulation of metabolic processes (such as oxidative phosphorylation).

The activation of these metabolic pathways may result in the rise of oxidative stress, which could explain the decrease in vitality and increase in mitophagy pathway observed in SARS-CoV-2–infected cells (see Table E1). Although we showed that primary hTECs were unable to sustain effective viral replication in an in vitro culture system (which is a finding observed in other cellular systems55,56), our data demonstrate that SARS-CoV-2 can persist in infected hTECs over time in vitro and in vivo.

Thus, along with the changes induced by the direct infection of cells, recirculating virus-specific T cells could target infected TECs and significantly contribute to thymic damage and reduced thymic output. Previous studies conducted on mouse models of mycobacterial and lymphocytic choriomeningitis virus (LCMV) infections support this hypothesis.57,58

Impaired thymic function in patients with COVID-19 could potentially lead to significant immunologic consequences. In addition to its vital importance in generating the T-cell pool during early life, optimal thymic function is required to reestablish T-cell immunity after periods of immunologic insults, such as those caused by antineoplastic therapies, immunosuppressive treatments, and infections.

Reduced thymic function and the resulting decrease in T-cell export could exacerbate lymphopenia in acutely ill patients with COVID-19 and increase the time required to restore the number and function of circulating T-cells after recovery. Delayed recovery of thymic function may contribute to the development of secondary infections, which can worsen the severity of the illness, increase the risk of disease progression,59 and facilitate persistent symptoms associated with herpesvirus reactivation.60

Furthermore, the direct impact of SARS-CoV-2 on TECs and the additional damage caused by the rise in proinflammatory molecules, such as interferons, IL-6, and TNF-α, which have all been implicated in acute thymic involution,61 could lead to suboptimal education of the developing thymocytes.

An impaired process of T-cell development might alter the process of central tolerance and generate the maturation of T-cell responses to self-antigens that lead to the development of autoimmune response against self-tissue antigens. The relationship between viral infections and the development of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and SLE, is well known.62

However, the underlying mechanisms of this association are still largely unexplored, although evidence suggests that molecular mimicry, bystander T-cell activation, and abnormal nucleic acid sensing may play a role.63,64 Breaching of central tolerance has been also proposed.

Several viruses, including HIV, measles virus, LCMV, yellow fever virus, and Zika virus, can cause thymic involution and altered thymic epithelium architecture and function.20,24,28,57,65,66 Recent evidence in mouse models of roseolovirus and LCMV infections demonstrated a direct link between viral infection and the development of autoimmunity67 and self-reactive T cells.57 SARS-CoV-2 infection generates a strong and excessive inflammatory response involving pathways and targets known to be commonly associated with autoimmune and inflammatory diseases.

Whether SARS-CoV-2 induces or exacerbates autoimmunity is an active area of research, particularly now that several reports on a potential association of COVID-19 with autoimmune diseases (such as idiopathic thrombocytopenic purpura, multisystem inflammatory syndrome in children, autoimmune thyroid disease, and Guillain−Barré syndrome) have gradually started to emerge.68

Lastly, studies in experimental mouse models have demonstrated that infections of the thymic microenvironment results in the emergence of pathogen-specific tolerance, as shown for LCMV, murine leukemia virus,69 hepatitis B virus,69 and Mycobacterium avium infections.70 However, whether this is relevant in human infections is a matter of investigation.

To the best of our knowledge, our studies are unique in establishing that SARS-CoV-2 can directly target the thymus and alter gene expression profile of thymic epithelium. We propose that the evaluation of thymic functionality (eg, by quantifying sjTRECs in patient peripheral blood) may be a useful marker to identify patients with COVID-19 at risk of complication both in acute and convalescent phases. Although the data that we have collected on altered expression of potential autoantigens are limited, our study also raises the possibility that disruption of thymic function by SARS-CoV-2 may be an additional mechanism to explain the excessive inflammation and potentially contribute to the development of autoimmune diseases related to COVID-19.
Clinical implications

Patients with COVID-19 have reduced thymic T-cell output, and disease severity is inversely correlated with thymic function. Monitoring thymic activity may be a useful marker to evaluate disease severity and progression.

We gratefully acknowledge the assistance of the Flow Cytometry Core; in particular, we thank Dr Ezio Giorda and Dr Gabriele Volpe. We also thank Dr Marco Pezzullo for support with the immunofluorescence assays. We particularly thank Dr Loredana Ruggeri (University of Perugia) for the insights and reagents for the setup of the hTEC culture system.

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