Scientists from the Josep Carreras Leukemia Research Institute and the Bellvitge Biomedical Research Institute (IDIBELL), say they have identified an epigenetic signature associated to the development of the Multisystem Inflammatory Syndrome in Children (MIS-C) after a SARS-CoV-2 virus infection. The signature has been named EPIMISC, in line with previous studies on the epigenetics of COVID-19 from the same team, which published this recent study, “Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study,” in eClinicalMedicine.
One of the puzzles of infection with the virus has been the remarkable resilience of children to exhibit severe COVID-19. However, a small percentage of the pediatric population affected by the virus experienced a serious health condition called MIS-C, also known as pediatric inflammatory multisystem syndrome (PIMS), that require admission to intensive care unit in around 60% of cases.
In MIS-C, different parts of the body can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. The factors associated with the appearance of MIS-C beyond the presence of the virus are unknown.
“Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention,” write the investigators.
“However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C.
“Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender, and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants.
“The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2.
“The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C.
“We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.”
“The COVID-19 disease in adults is characterized by difficulty breathing, while the studied rare syndrome associated with the same virus in children affects many more organs and can have severe consequences,” said Manel Esteller, MD, PhD, director of the Josep Carreras Leukemia Research Institute (IJC), ICREA Research Professor, and professor of genetics at the University of Barcelona. “As the bases for the disorder are unknown, we decided to compare the epigenome of healthy children, children with COVID-19 without MIS-C, and children with COVID-19 who experienced MIS-C.
“We found that MIS-C is characterized by a specific deregulation of epigenetic cellular programming that leads to a landscape of hyperinflammation that can damage tissues.”
The results of the study showed that specific genes were affected in patients, such as those associated with the activation of T lymphocytes, natural killer cells, the recognition of antigens and coagulation. This pattern of epigenetic deregulation was also observed in Kawasaki Syndrome, another inflammatory disease that peaked in 2009 and possibly linked to infection with the influenza virus A H1N1.
Interestingly, two of the 33 DNA methylation events that define the EPIMISC signature are also characteristic of adults without comorbidities who develop severe COVID-19 disease, as previously defined in the EPICOVID signature found by the same team last year.
This fact confirms that both processes, MIS-C in children and severe acute respiratory distress syndrome in adults, are inflammatory post-infectious complications and could be treated in a different way than the initial phase of the viral infection. On this regard, researchers hypothesize that pharmacological inhibition of the CUL2 gene, a mediator of inflammation, could be useful for MIS-C patients since it is known to protect against hyperinflammatory responses.
“It is interesting to see that two disorders that exhibit similar clinical manifestations, MIS-C and Kawasaki, also share a common epigenetic signature, which is different to the epigenetic signature caused by other viruses including HIV,” noted Aurora Pujol, MD, PhD, IDIBELL.
In the same line, Esteller concludes that “it seems that in both syndromes, MIS-C and Kawasaki, there is an exaggerated reaction of the children’s immune system against a viral attack. Knowing the mechanisms triggering both diseases will give us better tools to diagnose and treat them.”