Louise Malle, MD/PhD candidate, and Dusan Bogunovic, PhD
In April 2020, as the COVID-19 pandemic spread through New York City, Louise Malle, an MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, turned her focus to the disturbing statistics coming out on disease severity. She thought the data might inform her research to better understand immunity in people with Down syndrome.
Louise Malle, MD/PhD candidate
Ms. Malle, who works in the lab of Dusan Bogunovic, PhD, surveyed thousands of patients diagnosed with COVID-19, and essentially found that individuals with the syndrome have about 10 times the likelihood of having extremely severe disease.
Dr. Bogunovic is Professor at the Marc and Jennifer Lipschultz Precision Immunology Institute, The Mindich Child Health and Development Institute, the Icahn Genomics Institute, and the departments of Oncological Sciences, Microbiology, Pediatrics, and Dermatology, as well as a Director of the Center for Inborn Errors of Immunity—all at Icahn Mount Sinai.
It turns out that Ms. Malle’s epidemiological observation added to a body of literature that suggests that severe viral disease is a problem in Down syndrome. The work led to new findings, published online on October 14, 2022 in the journal Immunity, showing that people with Down syndrome have less frequent but more severe viral infections.
“As we all were caught in the COVID-19 pandemic, Louise saw what was going on in the clinic in people with Down syndrome (based on her review of hospital records),” said Dr. Bogunovic, senior study author. “She saw what was going on in the world and then came to the lab, ultimately figuring out, at least in part, why this understudied and underserved population experiences more severe viral infections across the board.”
According to the study, this phenomenon is caused by increased expression of genes that sense an antiviral cytokine, type I interferon (IFN-I), as they are encoded on chromosome 21. Elevated sensing of IFN-I lead to hyperactivity of the immune response initially, but the body overcorrects for this to reduce inflammation, leading to increased vulnerability later in the viral attack.
Dusan Bogunovic, PhD
“Usually too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections,” says Dr. Bogunovic. “What is unusual is that individuals with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts. Here, we discovered how this is possible.”
Down syndrome is typically caused by triplication of chromosome 21. The syndrome affects multiple organ systems, causing a mixed clinical presentation that includes varying degrees of intellectual disability, developmental delays, congenital heart and gastrointestinal abnormalities, and Alzheimer’s disease in older individuals. It is universally present across racial, gender, or socioeconomic lines in approximately 1 in 800 live births, although there is considerable variation worldwide.
Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased rates of hospitalization of people with the genetic disorder have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infections, according to the researchers.
“We have a lot more to do to completely understand the complexities of the immune system in Down syndrome,” said Ms. Malle, first author of the study. “We have here, in part, explained the susceptibility to severe viral disease, but this is only the tip of the iceberg.”