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Multiomic Study Identifies Drivers of Severe COVID-19 in Patients Under 50 Without Comorbidities

NEW YORK – An international team led by investigators in France and the US has unearthed an immune-related gene signature that coincides with severe COVID-19 in young and middle-aged patients with no apparent comorbidities.

"[W]ithin a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients," co-senior and co-corresponding authors Seiamak Bahram, a researcher at the University of Strasbourg, and Thomas Chittenden, an investigator at the Genuity AI Research Institute and Boston Children's Hospital, and their co-authors wrote, noting that "very few [COVID-19 severity] studies have targeted a young population with no comorbidities to reduce confounders that may also drive severity and mortality."

As they reported in Science Translational Medicine on Tuesday, the researchers used a combination of whole-genome sequencing, blood RNA sequencing, mass cytometry and shotgun proteomic analyses on blood plasma and peripheral blood mononuclear cells (PBMC), cytokine profiling, and immunophenotyping on 47 COVID-19 patients under the age of 50 who required mechanical ventilation and treatment in the intensive care unit, as well as 25 age-matched COVID-19 patients treated in a non-critical setting and 22 healthy uninfected individuals.

They noted that the COVID-19 patients enrolled in the study had been treated in France between March and April of 2020, prior to widespread corticosteroid treatment for SARS-CoV-2 infections.

"A comprehensive understanding of the immune responses to SARS-CoV-2 infection is fundamental to develop an explanation as to why some young patients without comorbidities progress to critical illness whereas others do not, a phenomenon that has been exacerbated with new viral variants in current epidemic waves across the globe," the authors explained. "In particular, knowledge of the molecular drivers of critical COVID-19 is urgently needed to identify predictive biomarkers and more efficient therapeutic targets that function through drivers of critical COVID-19 rather than to downstream or secondary events."

After using machine learning, artificial intelligence, and probabilistic programming strategies to analyze the multiomic data generated for the cases and controls, the team saw higher-than-usual levels of inflammation and coagulation factors in the critical COVID-19 cohort, as well as altered lymphoid and myeloid cell activation and molecular features related to viral activity.

"Altogether, the results indicate that critical illness was characterized by a proinflammatory cytokine storm and notable changes in the T, B, dendritic, and monocyte cell compartments," the authors reported. "These specific changes were independent from the extent of viral infection, as both the global anti-SARS-CoV-2 antibody concentrations and their neutralizing activity were not different in critical versus non-critical patients."

When they dug into the set of genes that were differentially expressed in samples from the critical COVID-19 cases, non-critical cases, and uninfected controls, the researchers found a gene signature associated with severe infection that also coincided with critical cases in a follow-up analysis of 81 more individuals with critical SARS-CoV-2 infections and another 73 individuals who had recovered from COVID-19.

Among the additional analyses performed, the team delved into the critical COVID-19 gene signature and related features to find potential driver genes. Of those, the top candidate was ADAM9, a gene encoding a metalloprotease and disintegrin that had elevated expression in the severe cases.

Indeed, the researchers' subsequent experiments pointed to a role for ADAM9 in SARS-CoV-2 uptake and replication in human lung epithelial cells, and the team found support for the critical COVID-19-related gene signature.

"Our results collectively demonstrate that ADAM9 is an in vivo upregulated driver in critical patients," the authors wrote. "We also show a higher global proteolytic activity in serum samples of critical patients and demonstrate that a higher amount of ADAM9 facilitates viral infection and replication in an ex vivo cellular model."

Still, they cautioned that the "predictive performance of ADAM9 as [a] diagnostic marker for disease severity, as well as [a] therapeutic target has to be evaluated in further studies."