Following the exposure of the same microorganism there are resistant subjects who develop asymptomatic or paucisymptomatic infections, and subjects who develop serious and potentially lethal infections. Human genomics studies have shown that some serious respiratory infections (e.g. rhinovirus, influenza pneumonia), may have a genetic cause, especially in individuals with no known predisposing conditions. Also during the COVID-19 pandemic, a variability of the clinical picture from SARS-CoV-2 infection was observed, suggesting that also in this case an influence of human genetic factors in the response to the virus may be implicated. Particularly in the pediatric field, although in most cases children infected with SARS-CoV2 have less severe forms than adults, it has been observed that about 0,6 percent of children showed a clinical picture characterized by a severe multisystem inflammatory response, called Multisystem Inflammatory Syndrome in Children or MIS-C. It has therefore been hypothesized that extreme phenotypes of SARS-Cov2 disease, such as MIS-C, may be more likely to be explained by a genetic defect of the antiviral response.
The study published in Science involved numerous countries and institutes aggregated in different consortia: the Buzzi Children's Hospital and the University of Milan joined the international consortium Covid Human Genetic Effort with the aim of identifying the underlying mechanism of the wide individual variability of protective immune responses against microorganisms during primary infection. Researchers explored, by exome sequencing, inborn errors of immunity underlying severe forms of COVID-19 and specifically forms of MIS-C in previously healthy pediatric subjects. The first results obtained by studying a large sample of children presenting MIS-C made it possible to identify recessive defective variants on the OAS1, OAS2 or RNASEL genes (implicated in the activation of OAS–RiboNuclease L, OASRNase L), involved in innate immunity and responsible for MIS-C in five unrelated children, 1% of the total population studied. OAS-RNase L deficient cells exhibit excessive inflammatory responses in response to SARS-CoV-2 infection.
“The results suggest that these deficits may influence antiviral responses also in cells of other tissues damaged during MIS-C, such as cardiomyocytes, enterocytes and endothelial cells. Expanding knowledge on the pathogenesis of the disease and induced organ damage will allow for the definition of personalized treatment pathways. The next steps of the research foresee further genetic and functional studies to define new pathogenetic variants responsible for serious forms of the disease” comments Prof. Gian Vincenzo Zuccotti, of the State University of Milan and head of the Department of Pediatrics at the Buzzi Children's Hospital in Milan, involved in the study with the pediatricians of his team.
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