Explaining the viral infection paradox in individuals with Down syndrome

Alternating hyper- and hypo-responsiveness to the potent cytokine IFN-I in individuals with Down syndrome outcomes in much less viral illness and elevated infection-related morbidity and mortality. Credit: Immunity/Malle et al.

New findings clarify why individuals with Down syndrome have fewer however extra extreme viral infections.

Viral infections are uncommon in individuals with Down syndrome. However, when current, these infections could cause critical sickness. New analysis findings present that this is because of elevated expression of the antiviral cytokine sort I interferon (IFN-I), which is partially encoded by chromosome 21. Elevated ranges of IFN-I initially result in a hyperactive immune response, however the physique overregulates this to scale back irritation, which then will increase vulnerability to viral assault. The end result was printed in the journal as we speak (October 14). immunity.

“We want extra to totally perceive the complexity of the immune system in Down syndrome.” — Louise Malle

“Usually an excessive amount of irritation signifies an autoimmune illness, and immune suppression usually signifies susceptibility to infections,” says senior researcher Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai. “Surprisingly, individuals with Down syndrome are infected and immunosuppressed, which is a paradox. Here we discovered the way it’s doable.”

Down syndrome is normally attributable to triplication of chromosome 21. This syndrome impacts a number of organ programs and causes a blended medical presentation, together with mental disabilities, developmental delays, congenital coronary heart and gastrointestinal issues, and[{” attribute=””>Alzheimer’s disease in older individuals.

Down syndrome is the most common chromosomal disorder. According to the CDC, each year, about 6,000 babies are born with Down syndrome in the United States. This is about 1 in every 700 babies born. Between 1979 and 2003, the number of babies born with Down syndrome increased by about 30% in the U.S. Older mothers are more likely to have a baby affected by Down syndrome than younger mothers.

Recently, it has become clear that atypical antiviral responses are another important feature of Down syndrome. Increased rates of hospitalization of people with Down syndrome have been documented for influenza A virus, respiratory syncytial virus, and severe acute respiratory syndrome due to coronavirus (

While people with Down syndrome show clear signs of immune disturbance, it has yet to be elucidated how a supernumerary chromosome 21 leads to dysregulation of viral defenses. To address this knowledge gap, the researchers compared fibroblasts and white blood cells derived from individuals with and without Down syndrome, at both the mRNA and protein levels. They focused on the potent antiviral cytokine IFN-I receptor subunits IFNAR1 and IFNAR2, which are located on chromosome 21.

The scientists discovered that increased IFNAR2 expression was sufficient for the hypersensitivity to IFN-I observed in Down syndrome, independent of trisomy 21. But subsequently, the hyper-active IFN-I signaling cascade triggered excessive negative feedback via a protein called USP18, which is a potent IFNAR negative regulator. This process, in turn, suppressed further responses to IFN-I and antiviral responses. Taken together, the findings unveil oscillations of hyper- and hypo-responses to IFN-I in Down syndrome, predisposing to both lower incidence of viral disease and increased infection-related morbidity and mortality.

“We have a lot more to do to completely understand the complexities of the immune system in Down syndrome,” says first author Louise Malle of the Icahn School of Medicine at Mount Sinai. “We have here, in part, explained the susceptibility to severe viral disease, but this is only the tip of the iceberg.”

Reference: “Excessive Negative Regulation of Type I Interferon Disrupts Viral Control in Individuals with Down Syndrome” by Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush and Dusan Bogunovic, 14 October 2022, Immunity.
DOI: 10.1016/j.immuni.2022.09.007

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