04.06.2023 Immunology

Antiviral paradox

Immune system molecule may explain why people with Down syndrome are simultaneously more resistant and more vulnerable to viral infections

American scientists conducted experiments using cell cultures from people with Down syndrome in an attempt to shed light on what makes them both more resistant and more vulnerable to viruses. | Credit: Léo Ramos Chaves

A team of researchers from the USA may have discovered what makes people with Down syndrome both more resistant and more vulnerable to viral infections. The mechanism appears to be linked to type 1 interferon signaling. An important part of the immune system, interferons act with greater or lesser intensity in individuals with Down syndrome due to the duplication of chromosome 21 that triggers the syndrome during embryonic development.

“Usually, too much inflammation means autoimmune disease, and immune suppression usually means susceptibility to infections,” said study coordinator Dusan Bogunovic of the Icahn School of Medicine at Mount Sinai Hospital, New York.

“What is unusual is that individuals with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts. In our research, we discovered how this is possible.” Bogunovic and colleagues published a paper on the subject in a recent issue of the journal Immunity.

In patients with the syndrome, it is common for two apparently contradictory situations to occur. They appear to experience certain types of infections, such as influenza A, shingles, and intestinal infections, significantly less frequently than the general population.

However, once infected with a pathogen, they often face an increased risk of complications, hospital admission, and death. This seems to be especially true for viruses that affect the respiratory tract, such as respiratory syncytial virus (RSV) and SARS-CoV-2.

Before the pandemic began in 2020, infections accounted for 20–40% of deaths in people with Down syndrome, while this figure was just 4.5% for the rest of the population.

“People with Down syndrome are both inflamed and immunosuppressed, a paradox of sorts,”

says Dusan Bogunovic of the Icahn School of Medicine, USA

This increased vulnerability to respiratory problems is likely partially linked to anomalies in the respiratory tract typical of the unique anatomy of people with Down syndrome. However, the authors of the new study also demonstrated that the extra copy of chromosome 21 that characterizes this population’s genome means they carry duplicated versions of genes important to the functioning of type 1 interferons.

These genes encode receptors to which the molecule binds on the surface of cells. Thus, as soon as a viral infection is detected by the body, the cells of people with Down syndrome are initially better able to react to the newly arrived pathogen through interferon activity. This was the outcome of the tests conducted by Bogunovic and his colleagues using cell cultures from people with the syndrome.

The problem is that the differences do not result only in a greater presence of interferon receptors. Analysis of gene activation patterns in cells from Down syndrome patients indicates that the receptors also affect a number of other genes in the same regulatory pathway as type 1 interferons. Paradoxically, this has a negative effect on the individual’s ability to fight viral infections.

Because interferon overactivation can have negative side-effects, such as triggering harmful inflammatory processes, the body has safeguards to mitigate the signaling of this pathway. One of them is the USP18 protein. In people with Down syndrome, everything indicates that this process occurs in excess after the type 1 interferon pathway is first activated so intensely.

The result is that when a virus re-invades their body, their defenses are weaker than the first time, leading to more severe infection and all the associated risks. This results in an alternation between what scientists call type 1 interferon hyperresponses and hyporesponses.

“We have a lot more to do to completely understand the complexities of the immune system in Down syndrome. In this study, we partly explained the susceptibility to severe viral disease, but this is only the tip of the iceberg,” concludes lead author Louise Malle.


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