Why This Unexpected Epstein-Barr Virus (EBV) Culprit is Found in Long-COVID Patients

Shin Jie Yong

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When it comes to herpesviruses, once infected, stay infected.

One unique trait of herpesviruses is the ability to stay latent (i.e., dormant) in the infected host for life. In this latent state, the herpesvirus is inactive, and no virus replication occurs. But in times of stress or immunosuppression, latent herpesvirus can reactivate, start replicating and cause problems.

Is long-Covid one of the symptoms of herpesvirus reactivation?

Studies have now found that might actually be the case in some but not all long-Covid cases — the culprit being Epstein-Barr virus (EBV), also known as human herpesvirus 4.

Biomarkers of EBV reactivation found in long-Covid

In a recent study conducted at Yale School of Medicine, Connecticut, U.S., Klein et al. performed sophisticated blood immune profiling and machine learning techniques to pinpoint what characterizes long-Covid — i.e., what biomarkers distinguish long-Covid from non-long Covid patients.

Klein et al. recruited 178 participants, consisting of 99 individuals with long-Covid, 40 uninfected healthy controls, and 39 convalescent controls. (Convalescent: previously infected with SARS-CoV-2 but recovered.)

Among individuals with prior Covid (long-Covid and convalescent groups), most were not hospitalized during their Covid period over a year ago.

And blood immune profiling revealed that:

  • Long-Covid group had dysregulated immunological activities involving monocytes, dendritic cells, activated B-cells and T-cells, exhausted T-cells, and certain interleukins compared to other groups.
  • Long-Covid group had lower cortisol levels compared to other groups, which, according to machine learning analyses, is the most significant predictor of long-Covid.
  • No differences in levels of over 6000 autoantibodies between groups.
  • Long-Covid group had higher antibody reactivities against 4 out of 225 virus proteins: EBV capsid protein gp23, EBV early D antigen, EBV glycoprotein gp42, and varicella-zoster virus (VZV) glycoprotein E:
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Long-Covid (LC) patients had higher antibody reactivities against four viral proteins than healthy and convalescent controls (HC and CC).Data adapted from Klein et al. (2022).

“Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation, and are less consistent with the autoantibodies to extracellular antigens,” Klein et al. wrote.

Notably, in the long-Covid group, antibody reactivity against EBV proteins correlated with markers of T-cell activation — indicating that latent EBV reactivation and chronic inflammation are closely intertwined.

As Klein et al. stated:

“Unexpectedly, subsets of Long COVID participants also had polyfunctional IL-4 / IL-6 co-expressing CD4+ T cells which correlated with antibody reactivity against EBV lytic antigens, but not SARS-CoV-2 antigens. In aggregate, these findings are consistent with chronic immune engagement against reservoirs of viral antigen among participants with Long COVID.”

Klein et al. aren’t the first to discover the link between EBV reactivation and long-Covid. Several other studies have also reported similar findings:

  • Peluso et al. (2022) demonstrated that increased antibody reactivity against EBV proteins — which also correlated with markers of pro-inflammatory cytokines — predicted the development of long-Covid.
  • Su et al. (2022) showed that increased plasma levels of EBV gene fragments— which correlated with markers of activated and exhausted T-cells — in Covid-19 patients predicted the development of long-Covid.
  • Rohrhofer et al. (2022) reported a higher rate of EBV DNA positivity in throat samples of long-Covid patients compared to non-long-Covid controls (50% vs. 20%).
  • Gold et al. (2021) found a higher rate of antibody reactivity against EBV proteins in long-Covid patients compared to non-long-Covid controls who recovered from Covid (67% vs. 10%).

In aggregate, several studies have found evidence of EBV reactivation and EBV-related immune abnormalities in some but not all long-Covid patients.

How EBV reactivation triggers diseases

Over 90% of the population worldwide has been infected with EBV at some point in their lives, especially during childhood, mainly via the oral route such as kissing and sharing eating utensils or food and drinks.

The first EBV infection can either cause disease symptoms indistinguishable from common childhood illnesses or no symptoms. In either case, EBV will enter a latent state in B-cells in the body forever. In this state, EBV may occasionally reactivate, which may or may not cause disease.

The disease EBV causes is infectious mononucleosis; possible symptoms are extreme fatigue, body aches, fever, sore throat, swollen lymph nodes, or rash. No vaccines or specific anti-virals exist for infectious mononucleosis other than general anti-pain or anti-fever medications, rest, and hydration.

Most people recover in 2–4 weeks. However, some may still have fatigue for several more weeks to months, possibly leading to chronic fatigue syndrome, which is also one of the possible diagnoses of long-Covid.

Repeated cycles of EBV latency and reactivation put the immune system on high alert. As a result, T-cells — which kill abnormal cells like virus-infected or cancerous cells — are continually activated but unsuccessful at eliminating the threat, ultimately leading to a perpetual state of T-cell exhaustion and chronic inflammation.

Thus, markers of EBV-related T-cell exhaustion and chronic inflammation are commonly seen in chronic diseases like cancer, multiple sclerosis, chronic fatigue syndrome, and, now, long-Covid.

Particularly in cancer and multiple sclerosis, EBV infection or reactivation has been postulated as one of their leading causes or causative agents.

Because EBV could prime B-cells to undergo abnormal growth rate and morphology changes, EBV is thought to cause about 1% of cancers worldwide, especially B-cell-related cancers.

Because EBV could prime B-cells to produce auto-antibodies that attack the neuronal myelin sheath, EBV can cause multiple sclerosis in some cases. A 20-year longitudinal study, for instance, has shown conclusively that EBV can trigger the development and is the leading cause of multiple sclerosis.

What all of these tell us about long-Covid

Similarly, researchers have begun to unearth the contribution of EBV to the pathogenesis of long-Covid. As discussed in the previous section, studies have found, quite consistently, evidence of EBV reactivation and EBV-related T-cell and B-cell abnormalities in some but not all long-Covid patients.

It’s important to note that not all long-Covid patients have EBV reactivation, and not all EBV reactivation will lead to long-Covid.

In figure 1 above, for example, each dot denotes the data point of an individual case. Some dots between the long-Covid and control groups overlap, indicating no differences in EBV reactivation markers in those cases.

Therefore, aside from Covid-19, it’s unlikely that one true cause of long-Covid exists. Long-Covid is a multifactorial syndrome stemming from multiple disease-related biological factors, one of which is EBV reactivation.

Further analyses by Peluso et al. revealed that antibody reactivity against EBV proteins predicted the development of fatigue and neurological symptoms of long-Covid but, intriguingly, not the cardiopulmonary and gastrointestinal symptoms. This finding suggests that EBV may be responsible for certain subtypes of symptomatic patterns of long-Covid.

At the same time, because EBV is also closely tied to many other diseases — such as B-cell-related cancers, multiple sclerosis, and other autoimmune diseases — it’s possible that long-Covid patients may develop these EBV-related diseases later. But this hypothesis has not yet been studied.

As Klein et al. noted, “Whether EBV reactivation may also predispose people with Long COVID to the development or exacerbation of autoimmune pathologies, as has been recently reported for people with multiple sclerosis, will require extensive longitudinal monitoring and surveillance…”

EBV, therefore, might be a bigger microbial foe than we thought.

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