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Review
. 2023 Jan 31;15(2):400.
doi: 10.3390/v15020400.

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Affiliations
Review

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

Aristo Vojdani et al. Viruses. .

Abstract

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.

Keywords: EBV; HHV-6; autoimmunity; gut microbiota; long COVID; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); viral reactivation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Major factors that may be involved in the pathophysiologic mechanism of long COVID disease. This figure illustrates that long COVID is a multi-factorial disease, and that SARS-CoV-2, EBV and HHV-6 are viral contributors to its development, progress, duration and/or severity.
Figure 2
Figure 2
The 5 hypothesized mechanisms of long COVID disease.
Figure 3
Figure 3
How SARS-CoV-2 spreads throughout the body: infection, replication, and spread.
Figure 4
Figure 4
Viral enhancement hypothesis. In this figure, we propose that EBV and HHV-6 lytic replication induces change in ACE expression so as to increase the binding between the SARS-CoV-2 S-protein and the ACE2 receptor, thus enhancing SARS-CoV-2 binding to epithelial cells. (A) Just SARS-CoV-2, three spike proteins bind to ACE-2. Infection with SARS-CoV-2 causes a cell expression of ACE-2 receptor that matches with 3 spikes on the SARS-CoV-2 virus. (B) SARS-CoV-2 + EBV, four spike proteins bind to AC E-2. Infection with SARS-CoV-2 and EBV causes an expression of the ACE-2 receptor that matches 4 spikes on the virus. (C) SARS-CoV-2 + EBV + HHV-6, five spike proteins bind to ACE-2. Infection with SARS-CoV-2, EBV and HHV-6 causes expression of ACE-2 receptor that binds to the virus with 5 spikes for a perfect match.
Figure 5
Figure 5
The exposome factor or lifetime exposure to internal and external triggers (in this example, specifically SARS-CoV-2) may affect the reactivation of dormant viruses and cause the release of their viral dUTPases, which in turn can affect the humoral and cell-mediated components of the immune system, resulting in the activation of dendritic cells, Th1, Th17 and NKT cells. This may result in the production of many inflammatory cytokines and antibodies that together contribute towards ME/CFS and long COVID.
Figure 6
Figure 6
Enriched bacteria and fungi positively associated with long COVID or PACS versus depleted bacteria negatively associated with long COVID.
Figure 7
Figure 7
Epstein–Barr virus and a few of its associated autoimmune diseases.
Figure 8
Figure 8
HHV-6 virus and a few of its associated autoimmune diseases.

References

    1. Sun Y., Dong Y., Wang L., Xie H., Li B., Chang C., Wand F.-S. Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience. J. Autoimmun. 2020;112:102473. doi: 10.1016/j.jaut.2020.102473. - DOI - PMC - PubMed
    1. Setiati S., Harimurti K., Safitri E.D., Ranakusuma R.W., Saldi S.R.F., Azwar M.K., Marsigit J., Pitoyo Y., Widyaningsih W. Risk factors and laboratory test results associated with severe illness and mortality in COVID-19 patients: A systematic review. Acts Med. Indones. 2020;52:227–245. - PubMed
    1. Kifer D., Bugada D., Villar-Garcia J., Gudelj I., Menni C., Sudre C., Vuckovic F., Ugrina I., Lorini L.F., Posso M., et al. Effects of environmental factors on severity and mortality of COVID-19. Front. Med. 2021;7:607786. doi: 10.3389/fmed.2020.607786. - DOI - PMC - PubMed
    1. Vojdani A., Vojdani E., FRosenberg A.Z., Shoenfeld Y. The role of exposomes in the pathophysiology of autoimmune diseases II: Pathogens. Pathophysiology. 2022;29:243–280. doi: 10.3390/pathophysiology29020020. - DOI - PMC - PubMed
    1. Rappaport S.M., Smith M.T. Epidemiology, environment and disease risks. Science. 2010;330:460–461. doi: 10.1126/science.1192603. - DOI - PMC - PubMed