Scientists reveal how Epstein-Barr virus reactivation triggers MIS-C in children

Why are some children devastated by mysterious post-COVID inflammation? Scientists uncover how a ‘silent’ virus awakens – and a promising path to stop it.

Study: TGFβ links EBV to multisystem inflammatory syndrome in children. Image Credit: Kateryna Kon / Shutterstock

A new study published in the journal Nature reveals a potential mechanism associated with the development of multisystem inflammatory syndrome in children (MIS-C), which is a rare but severe condition of hyperinflammatory shock triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

The study suggests that TGFβ-induced immune suppression leads to Epstein-Barr virus (EBV) reactivation, which in turn contributes to the hyperinflammatory state seen in MIS-C.

Background

Multisystem inflammatory syndrome in children (MIS-C), a state of extreme inflammation, typically affects children at four to eight weeks after acute SARS-CoV-2 infection. The disease can be life-threatening if left untreated.

SARS-CoV-2 typically induces asymptomatic or mildly symptomatic infection in children. However, in some rare cases, the immune system of affected children can be hyperactivated, leading to heart failure, skin rashes, high fever, and ultimately multi-organ failure.

Existing evidence suggests that MIS-C is associated with the expansion and activation of a unique subset of T cells known as TCRVβ21.3+ T cells, which might bind to a superantigen-like region within the spike protein of SARS-CoV-2. However, more recent research, including pre-coronavirus disease 2019 (COVID-19) pandemic evidence, indicates that the spike protein is not required for the TCRVβ21.3+ T cell expansion in MIS-C and that alternative triggers, such as latent viral reactivation, may be involved. In particular, this study identifies EBV reactivation, enabled by immune suppression, as a key factor driving TCRVβ21.3+ T cell expansion. Despite extensive research, the exact cause of MIS-C remains largely unknown.

Researchers at Charité – Universitätsmedizin Berlin and the Leibniz Institute German Rheumatism Research Center (DRFZ) conducted a study to more conclusively understand the pathogenesis of MIS-C.

This multi-center study involved six centers across four continents, including 145 patients with MIS-C and 221 pediatric controls who also had SARS-CoV-2 infection but did not develop MIS-C.

Study findings

The study reported that the combination of TGFβ-driven immune suppression and subsequent reactivation of a preexisting, dormant infection with the Epstein-Barr virus (EBV) is responsible for driving the extreme inflammatory responses that occur in MIS-C patients.

EBV infection is very common, affecting approximately 90% of people at some point in their lifetime. The virus causes glandular fever that exhibits flu-like symptoms. It can remain dormant in the body for years without causing infection.

Tilmann Kallinich, the study’s lead researcher and the head of a liaison working group at the DRFZ, said, “Even after acute infection has been overcome, the virus is not yet eliminated from the body. The Epstein-Barr virus nests in various cells of the body and thus evades the immune system. In this way, it survives in humans for a lifetime. It can flare up again years after the initial infection, for example, if the immune system is weakened.”

Researchers identified EBV in the blood samples derived from children with MIS-C. They also found antibodies and large amounts of EBV-reactive memory T cells in affected children, indicating the reactivation of their immune systems to fight against the virus.

Specifically, they examined T cell receptor repertoires of children with MIS-C and observed expansion of T cells expressing TCRVβ21.3, closely resembling EBV-reactive T cell clones that are normally responsible for eliminating EBV-infected B cells. This finding challenges earlier hypotheses that suggested SARS-CoV-2 spike protein might act as a superantigen driving this T cell expansion.

Dr. Mir-Farzin Mashreghi, deputy scientific director at the DRFZ and a co-lead researcher of the study, explained, “We also discovered that while the immune cells are fighting the Epstein-Barr virus, they are fighting with blunt weapons, so to speak. The immune cells are no longer able to kill the EBV-infected body cells.”

Researchers found that in response to SARS-CoV-2 infection, a large amount of transforming Growth Factor beta (TGFβ) is produced in children’s bodies. TGFβ is an anti-inflammatory molecule that inhibits the activity of immune cells, particularly cytotoxic T cells that would normally control EBV, leading to suppressed immune responses against EBV. TGFβ also affects monocytes and B cells, reducing their ability to present antigens and activate other parts of the immune system. These observations explain why the immune system of children with MIS-C fails to fight against the virus despite reactivation.

In addition to suppressing T cell function, TGFβ also downregulates antigen presentation in monocytes, further contributing to immune dysfunction and inflammation in MIS-C.

“In some children, the coronavirus infection triggers a system that escalates: The messenger substance TGFβ prevents the immune cells from keeping the Epstein-Barr virus in check, allowing it to multiply again. The body then produces more immune cells to fight the virus, but these remain nonfunctional. This ultimately culminates in an extreme inflammatory reaction that can damage organs and be potentially fatal”, explained Dr. Mir-Farzin Mashreghi.

Discovery of a potential therapeutic strategy for MIS-C

Anti-inflammatory medicines, including immunoglobulins or cortisone preparations, are primarily used to inhibit hyperinflammatory responses in patients with MIS-C. These medicines can effectively cure most patients with MIS-C.

Researchers here found that TGFβ-induced reactivation of EBV in patients with MIS-C can be reversed by blocking TGFβ. In laboratory experiments, the use of TGFβ inhibitors restored T cell function and reduced EBV reactivation. They believe that TGFβ inhibitors can potentially treat MIS-C, as well as other severe long-term consequences of SARS-CoV-2 infection.

However, they caution that further clinical studies are necessary to determine the safety and efficacy of TGFβ inhibitors in children with MIS-C.

Dr. Mir-Farzin Mashreghi stated, “Perhaps there are parallels here to the processes in MIS-C, in which case TGFβ inhibitors would be potential candidates for therapy against long COVID. We also know that high TGFβ levels in adults are associated with severe COVID-19 courses. We therefore suspect that the course of COVID-19 disease can be beneficially influenced by TGFβ blockade.”

The study also revealed that children with MIS-C had a significantly higher rate of EBV seropositivity (around 80%) compared to age-matched healthy controls (about 50%), suggesting that prior EBV infection is a major risk factor for developing MIS-C following SARS-CoV-2 infection.

Given the study findings, researchers highlight the need for future research to determine the therapeutic efficacy of TGFβ inhibitors in SARS-CoV-2-related illnesses.