Scientists discover mechanisms that could explain high risk of complications from lung infections in Down syndrome

AURORA, Colo. (August 2, 2023) – Individuals with Down syndrome, the genetic condition caused by triplication of human chromosome 21, also known as trisomy 21, display a very high risk of hospitalization and mortality after developing lung infections. Respiratory disease is second only to congenital heart defects as a cause of death among children with Down syndrome, and lower respiratory tract pathology is the most common cause of acute hospital admissions in this population. Furthermore, adults with Down syndrome have a much higher risk of hospitalization and death from COVID-19. Despite many research efforts, the mechanisms by which trisomy 21 causes these effects have been unclear.

In a recent publication, a multidisciplinary team of scientists at the University of Pittsburgh, the Linda Crnic Institute for Down Syndrome (Crnic Institute) at the University of Colorado, and the Icahn School of Medicine at Mount Sinai in New York report a series of studies illuminating two major mechanisms underlying high risks from lung infections in Down syndrome: poor ciliary function and immune hyper-reactivity.

The research team, led by Kambez H. Benam, PhD, completed a series of experiments using a sophisticated cell culture system mimicking the conditions of the airway lining as well as a mouse model of Down syndrome. The first key observation from the cell culture experimental paradigm was that the trisomy impairs the number and function of the cellular appendages known as cilia in key airway lining cells. Cilia, which are motile cellular protrusions with key functions in the movement of fluids and clearance of debris outside the cell, were found in fewer numbers and to beat with less frequency in cells with triplicated genes. “This defect in ciliary function could decrease the capacity of the respiratory tract to clear mucus and viral particles, thus likely to affect the biodynamics of the upper airway during a viral infection, potentially leading to dangerous accumulation of fluids in the lung,” explains Dr. Benam.

The second key observation from these experiments is that, when exposed to a common influenza virus strain, cells with triplicated genes over-produced many inflammatory molecules, including factors involved in the recruitment of immune cells into the lung. Although cells with triplicated genes produced the same number of viral particles, their immune reaction was clearly exacerbated. “This immune over-reaction could be very dangerous during a lung viral infection, leading to massive immune infiltrates that cause more harm than good, eventually compromising lung function,” describes Kelly Sullivan, PhD from the Crnic Institute and co-author of the study.

The new results illuminate potential strategies to counteract the harmful effects of trisomy 21 during a lung infection. “These results contribute to a growing body of evidence indicating that immune hyper-reactivity can cause many health issues in Down syndrome and justifies the testing of therapies that could restore immune balance in this population,” says Joaquin Espinosa, PhD, Executive Director of the Crnic Institute and co-author of the study. “We are currently performing clinical trials testing a class of immune-modulatory medicines known as JAK inhibitors for multiple therapeutic endpoints in Down syndrome, and the new results from this study indicate that these medicines could improve lung health, even during a viral infection, as it has been demonstrated in the general population when JAK inhibitors were approved for severe COVID-19 cases during the pandemic.”

The research team has identified many important future directions, including the analysis of other lung pathogens as well as the testing of diverse immune-modulatory agents in the mouse model and in advanced cell-based models of Down syndrome. “We look forward to making additional important contributions to the understanding of lung health and disease in Down syndrome, with clear potential to benefit this population across the lifespan,” says Dr. Benam.

About the University of Colorado Anschutz Medical Campus

The University of Colorado Anschutz Medical Campus is a world-class medical destination at the forefront of transformative science, medicine, education and patient care. The campus encompasses the University of Colorado health professional schools, more than 60 centers and institutes and two nationally ranked independent hospitals - UCHealth University of Colorado Hospital and Children's Hospital Colorado - that treat more than two million adult and pediatric patients each year. Innovative, interconnected and highly collaborative, the University of Colorado Anschutz Medical Campus delivers life-changing treatments, patient care and professional training and conducts world-renowned research fueled by over $690 million in research grants. For more information, visit www.cuanschutz.edu.

About the Linda Crnic Institute for Down Syndrome 

The Linda Crnic Institute for Down Syndrome is one of the only academic research centers fully devoted to improving the lives of people with Down syndrome through advanced biomedical research, spanning from basic science to translational and clinical investigations. Founded through the generous support and partnership of the Global Down Syndrome Foundation, the Anna and John J. Sie Foundation, and the University of Colorado, the Crnic Institute supports a thriving Down syndrome research program involving over 50 research teams across four campuses on the Colorado Front Range. To learn more, visit www.crnicinstitute.org or follow us on Facebook and Twitter @CrnicInstitute. 

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