Review identifies future research directions for the study of a SARS-CoV-2 reservoir in PASC

By Tarun Sai LomteSep 6 2023Reviewed by Sophia Coveney

A recent study published in Nature Immunology reviewed the evidence for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reservoir in post-acute sequelae of coronavirus disease 2019 [COVID-19] (PASC).

Some individuals infected with SARS-CoV-2 develop new symptoms or sequelae, which do not resolve for months or years. This condition is known as PASC or long COVID. The enormous burden of PASC on pediatric and adult populations warrants delineating its core biological drivers.

In the present study, researchers explored the evidence for SARS-CoV-2 reservoir in PASC.

SARS-CoV-2 reservoir in PASC

Multiple studies have detected SARS-CoV-2 RNA and protein in tissues collected weeks or months post-COVID-19. Although many of these studies were not designed to evaluate PASC symptoms, they provided evidence that the virus can persist in reservoirs. The lack of PASC-specific autopsy data is a major limitation; thus, most evidence comes from studies on viral proteins in plasma and biopsies.

One biopsy study revealed that 70% of participants had SARS-CoV-2 RNA in the intestinal mucosa, and more than half harbored the viral nucleocapsid protein in intestinal epithelium seven months post-COVID-19. Viral protein or RNA persistence was associated with PASC symptoms but unrelated to COVID-19 severity and immunosuppressive therapy. In addition, numerous studies have reported the presence of SARS-CoV-2 proteins in plasma months after COVID-19.

These proteins are likely derivatives of the reservoir sites that leak into circulation. Besides, SARS-CoV-2 proteins have been detected in extracellular vesicles in PASC plasma. The presence of viral proteins up to 16 months post-infection suggests that some PASC patients might have a replicating virus. However, SARS-CoV-2 protein levels differ across studies, indicating that the activity/size of SARS-CoV-2 reservoirs might vary among patients.

The variability in detecting viral proteins in PASC plasma may reflect differences in viral translational activity. For instance, in a study, SARS-CoV-2 spike was detected in plasma from an individual only at some time points but not always. This suggests that SARS-CoV-2 in a reservoir could exhibit periods of inactivity and resume replication or protein synthesis when immune control is altered, consistent with fluctuating symptoms reported by PASC patients.

Disease mechanisms

Persistent SARS-CoV-2 proteins and RNA may engage with pattern-recognition receptors, triggering cytokine synthesis and inflammation. Repeated recognition could cause effector activity, altered differentiation, and exhaustion of virus-specific B and T lymphocytes over time, possibly contributing to pathology. Persistent viral proteins and active replication could also be cytopathic.

Nevertheless, SARS-CoV-2 proteins and RNA could drive PASC through mechanisms that may not result in overt inflammation and tissue cytopathology. Several proteins of the virus can downregulate host innate immunity and modulate genetic, epigenetic, and metabolic factors to dysregulate host signaling pathways in a way that drives chronic symptoms without cytopathology.

Immune dysregulation by SARS-CoV-2 reservoir may also reactivate latent infections.

SARS-CoV-2 reservoir, dysbiosis, and neurodegenerative sequelae

Infection by RNA viruses correlates with the outgrowth of opportunistic microbes and alterations in the microbiome, suggesting that host immune dysregulation by SARS-CoV-2 could negatively affect the activity and diversity of the host microbiome. Dysbiosis can lead to various pathologic conditions, given that microbiome-derived metabolites regulate host immune, hormonal, and metabolic signaling.

Microbiome activity aids in priming the host immune system, and dysbiosis could predispose individuals to altered SARS-CoV-2 clearance. Dysbiosis and SARS-CoV-2 reservoir may be accompanied by local low-grade inflammation promoting breakdown or dysfunction of the epithelial barrier. This increased barrier permeability may facilitate the translocation of microbial products and SARS-CoV-2 proteins into the bloodstream.

SARS-CoV-2 infection of the vagus nerve or reservoirs in sites innervated by the vagus nerve could activate localized paracrine signaling, resulting in ongoing sickness response symptoms in infected subjects. The persistence/infiltration of SARS-CoV-2 in the central nervous system potentially drives neuroinflammation and neurologic, psychiatric, and cognitive symptoms in PASC.

Concluding remarks

SARS-CoV-2 reservoirs may drive neuroimmune, microbiome, inflammatory, and coagulation abnormalities in PASC. Future studies should investigate whether the persistence of SARS-CoV-2 varies by anatomical location, cell type, or viral variant, as well as the mechanisms by which the virus escapes immunity to linger in human tissues.

Moreover, further investigation is required to ascertain whether the viral RNA in reservoirs is under active replication, transcription, or translation. Overall, studying SARS-CoV-2 reservoirs and associated factors in PASC will help delineate disease mechanisms and identify biomarkers and therapeutics.