New research reveals that Epstein-Barr virus reactivation, triggered by COVID, may cause MIS-C in children.
MIS-C is a severe inflammatory condition that can develop in children weeks after a COVID infection, sometimes with life-threatening consequences. Until now, its exact cause remained unclear. Researchers from Charité – Universitätsmedizin Berlin and the German Rheumatology Research Center (DRFZ), part of the Leibniz Association, have discovered that the condition is triggered by the reactivation of Epstein-Barr virus (EBV), a common virus that can remain dormant in the body. Their findings, published in Nature, provide crucial insights that could lead to new treatment approaches—not just for MIS-C, but potentially for other post-viral complications as well.
Mysterious Post-COVID Immune Reactions in Children
Most children who contract COVID experience only mild symptoms. In rare cases, however, some develop severe illness. Even children who have mild or no symptoms can, weeks later, experience an immune system overreaction that attacks their organs. This condition, known as Multisystem Inflammatory Syndrome in Children (MIS-C), can cause heart problems, skin rashes, and high fever. In serious cases, hospitalization is required to stabilize the immune system and prevent organ failure. About half of affected children require intensive care. Until now, the exact cause of MIS-C remained unclear.
“Discussions around the potential causes of MIS-C included the coronavirus surviving in the body, for example, or the immune system turning on itself,” says Prof. Tilmann Kallinich, Head of the Division of Rheumatology in the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité, and one of the study’s two lead authors.
“We’ve now found indications, however, that a resurgence of a second pathogen, the Epstein-Barr virus, is responsible for the inflammatory shock. Put simply, it wakes up from a dormant state because the COVID infection has thrown the child’s immune system in such disarray that it becomes unable to keep the dormant infection in check.”
Infection with Epstein-Barr Virus Flares Up Again
Epstein-Barr virus (EBV), the cause of glandular fever (also known as infectious mononucleosis or “mono”), is a common infection. While some people experience flu-like symptoms and prolonged fatigue, most don’t even realize they have it. In fact, about 90% of people will be infected at some point in their lives.
“Following an acute infection, however, the virus is not removed from the body,” explains Tilmann Kallinich, who also leads a liaison working group at the DRFZ. “The Epstein-Barr virus settles in different cells in the body, thereby escaping the immune defenses. Consequently, it remains in an infected person’s body for the rest of their life. The virus can flare up again years after the initial infection, including when immune systems are weakened.”
The research team has now identified a flare-up of an Epstein-Barr viral infection in children with MIS-C. The study examined 145 children aged between 2 and 18 years old who had been treated for MIS-C at the Children’s Hospital at Charité or at hospitals in Lyon (France), Naples (Italy), Ankara (Türkiye), and Santiago (Chile).
By way of comparison, the study also examined 105 children who went through a COVID infection without developing MIS-C. The researchers found traces of the Epstein-Barr virus in the blood of children with MIS-C, along with antibodies and high levels of specific immune cells against the virus – indicating that the body is actively fighting the pathogen.
Reactivation Trigger: The Messenger Substance TGFβ
“We’ve also determined that, although the immune cells set out to fight off the Epstein-Barr virus, they’re effectively fighting with blunt weapons,” explains Dr. Mir-Farzin Mashreghi, Deputy Scientific Director of the DRFZ and a researcher at the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité. Dr. Mashreghi spearheaded the study alongside Prof. Kallinich.
“The immune cells are no longer able to kill off body cells infected with EBV.” The researchers were able to attribute this inability to unusually high levels of a messenger substance called transforming growth factor beta (TGFβ), which the child’s body produces as a result of the COVID infection. TGFβ is a molecule that suppresses inflammation, inhibits the function of immune cells, and thus curbs their ability to attack the Epstein-Barr virus.
“In some children, COVID triggers a rapidly intensifying system: the messenger substance TGFβ prevents immune cells from keeping the Epstein-Barr virus in check, which enables the virus to proliferate again,” says Dr. Mashreghi, summarizing the new insights into the causes of MIS-C.
“In response, the body produces more immune cells to fight the virus, but these immune cells are still not functional. This culminates in an extreme inflammatory response that damages organs and can, potentially, be fatal.”
TGFβ Blockade Emerges as a Potential Treatment
The inflammatory cascade can be interrupted effectively with hospital medication, and the vast majority of children recover from MIS-C. To date, anti-inflammatory drugs such as immunoglobulins and cortisone-based preparations have been deployed to treat MIS-C.
“Our insights suggest that an early and targeted blockade of TGFβ could help to treat MIS-C,” summarizes Kallinich. “However, these new insights could also be relevant for the treatment of other COVID-related conditions.”
There are indications, for example, that reactivation of dormant viruses could play a role in long COVID. “There could be parallels with the processes at work in MIS-C, which would make TGFβ inhibitors potential candidates for a treatment for long COVID,” says Mashreghi.
“Furthermore, we know that high TGFβ levels in adults correlate with severe cases of COVID-19. We therefore suspect that a TGFβ blockade could have a positive influence on the course of COVID-19.” Further studies are now required to ascertain whether TGFβ inhibitors prove effective treatments for COVID-related illnesses.
Reference: “TGFβ links EBV to multisystem inflammatory syndrome in children” by Carl Christoph Goetzke, Mona Massoud, Stefan Frischbutter, Gabriela Maria Guerra, Marta Ferreira-Gomes, Frederik Heinrich, Anne Sae Lim von Stuckrad, Sebastian Wisniewski, Jan Robin Licha, Marina Bondareva, Lisa Ehlers, Samira Khaldi-Plassart, Etienne Javouhey, Sylvie Pons, Sophie Trouillet-Assant, Yasemin Ozsurekci, Yu Zhang, Maria Cecilia Poli, Valentina Discepolo, Andrea Lo Vecchio, Bengü Sahin, Murielle Verboom, Michael Hallensleben, Anja Isabelle Heuhsen, Camila Astudillo, Yazmin Espinosa, Maria Cecilia Vial Cox, Kerry Dobbs, Ottavia M. Delmonte, Gina A. Montealegre Sanchez, Mary Magliocco, Karyl Barron, Jeffrey Danielson, Lev Petrov, Nadine Unterwalder, Birgit Sawitzki, Mareen Matz, Katrin Lehmann, Alexander Gratopp, Horst von Bernuth, Lisa-Marie Burkhardt, Niklas Wiese, Lena Peter, Michael Schmueck-Henneresse, Leila Amini, Marcus Maurer, Jobst Fridolin Roehmel, Benjamin E. Gewurz, Lael M. Yonker, Mario Witkowski, Andrey Kruglov, Marcus Alexander Mall, Helen C. Su, Seza Ozen, Andreas Radbruch, Alexandre Belot, Pawel Durek, Tilmann Kallinich and Mir-Farzin Mashreghi, 12 March 2025, Nature.
DOI: 10.1038/s41586-025-08697-6
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