Inflammation and Epstein-Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection

Abstract

Recent studies have strengthened the evidence for Epstein-Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV⁺ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood-brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV⁺ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

Keywords: COVID-19; Epstein–Barr virus; PASC; inflammation; multiple sclerosis; post-acute sequelae of COVID-19 infection.

Figure 1

Inflammation at the intersection of EBV, MS, SARS-CoV-2, and PASC. EBV latent and lytic states can cause inflammation, and assembly/activation of the inflammasome can reactivate EBV. Neuronal demyelination contributes to MS, but EBV also contributes to MS through T cell exhaustion and molecular mimicry where latent or lytically infected B lymphocytes instigate immune dysregulation. SARS-CoV-2 activates the inflammasome and elicits inflammatory responses, which may trigger chronic inflammation, contributing to PASC. Chronic inflammation may also lead to BBB breakdown, which precipitates and/or exacerbates MS. Image created in BioRender.com accessed on 11 April 2023.

Figure 2

Innate and adaptive immune cells play a role in maintaining a state of inflammation frequently characterized by increased levels of cytokines. Some PASC patients have higher levels of neutrophils, which could promote an inflammatory state as they produce cytokines and are recruited by them. High levels of primed neutrophils have been observed in MS patients. Macrophages can have an anti-inflammatory effect early in MS, but as they become glutted with myelin, they can adopt a foamy, pro-inflammatory phenotype. Macrophages could also promote inflammation in MS via EBV exosomes. Macrophages may support inflammation in PASC through the production of cytokines and subsequent recruitment of more macrophages. Monocytes may have a pro-inflammatory effect in MS, especially by weakening the blood–brain barrier early in the disease. Monocytes in PASC patients may carry viral antigens long after the initial infection has resolved; higher numbers of pro-inflammatory classical monocytes were observed in some PASC patients early in recovery. T cells high in TNFα are carried by some PASC patients, which could provoke inflammation. In MS, T cells are known to recruit many other cell types into the brain and maintain a heightened state of inflammation that leads to plaque formation. B cells contribute to MS through molecular mimicry. Similarly, B cell production of autoantibodies to levels that are harmful could drive tissue damage and an increase in cytokines from damaged cells. B cells themselves are also known to produce cytokines. Image created in Biorender.com accessed on 11 April 2023.