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Review
. 2024 May 8;13(5):388.
doi: 10.3390/pathogens13050388.

The Potential Role of Viral Persistence in the Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

Lorenzo Lupi  1 , Adriana Vitiello  1 , Cristina Parolin  1 , Arianna Calistri  1 , Alfredo Garzino-Demo  1   2   3
Affiliations
Review

The Potential Role of Viral Persistence in the Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

Lorenzo Lupi et al. Pathogens. .

Abstract

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated not only with the development of acute disease but also with long-term symptoms or post-acute sequelae of SARS-CoV-2 (PASC). Multiple lines of evidence support that some viral antigens and RNA can persist for up to 15 months in multiple organs in the body, often after apparent clearance from the upper respiratory system, possibly leading to the persistence of symptoms. Activation of the immune system to viral antigens is observed for a prolonged time, providing indirect evidence of the persistence of viral elements after acute infection. In the gastrointestinal tract, the persistence of some antigens could stimulate the immune system, shaping the local microbiota with potential systemic effects. All of these interactions need to be investigated, taking into account predisposing factors, multiplicity of pathogenic mechanisms, and stratifying populations of vulnerable individuals, particularly women, children, and immunocompromised individuals, where SARS-CoV-2 may present additional challenges.

Keywords: PASC; SARS-CoV-2 persistence; dysbiosis; post-acute sequelae of SARS-CoV-2.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Timeline of SARS-CoV-2 nucleic acids or antigen detection after the acute phase of the disease. References are as follows: day 14 [24], day 70 [25], day 76 [30], day 120 [28], day 210 [28], day 221 [33], day 230 [30], day 280 [31], day 450 [34]. Created with BioRender.com.
Figure 2
Figure 2
(A) Schematic representation of B cells, antigen receptors, and antibodies. (B) Schematic representation of B cell development and maturation. B cells originally develop in the bone marrow, where through gene recombination, they develop a specific antigen receptor on its membrane (B cell receptor, BCR). Subsequently, B cells migrate to a secondary lymphoid organ where they can become activated upon binding their cognate antigen, secreting IgM. B cells can internalize and process the antigen, presenting it in the context of Class II MHC to CD4 T-cells. Upon recognition of their cognate antigen, it can stimulate B cells (T-dependent B cell activation), inducing the class–switch recombination process, first leading to the switch of the antibody isotype from IgM or IgD to IgE, IgA, or IgG. Further stimulation of B cells from the cognate antigen induces the somatic hypermutation process, leading to the development of antibodies with higher affinity to the specific antigen. Created with BioRender.com.
Figure 3
Figure 3
The persistence of SARS-CoV-2 nucleic acid or antigen can stimulate and activate the immune system, leading to a persistent inflammatory state, causing tissue damage, and possibly impairing the function of the CNS. The persistence of antigens or NA in the gastrointestinal system can cause a dysbiosis that can further enhance the inflammatory state or the gut–brain axis (GBA) has an impact on the CNS. Finally, viral antigens can stimulate the formation of microclots, causing damage to endothelium and tissue. Created with BioRender.com.
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Grants and funding

This study was supported by the Italian Ministry of University, project of relevant national interest (PRIN): 2020LW7X.

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