Upregulation of ADAM9 is a Driver of Severe Forms of COVID-19 in Younger Patients

Upregulation of ADAM9 is a Driver of Severe Forms of COVID-19 in Younger Patients

It has been almost two years since the SARS-CoV-19 virus was first detected and COVID-19 cases started to be identified around the world. Extensive research has been conducted into the mechanisms of action of the novel coronavirus and vaccines have been developed and have been rolled out globally, but little is known about the triggers of severe cases of COVID-19.

Age is certainly a factor, as are comorbidities, but there have been many younger individuals who have suffered from severe COVID-19 where no comorbidities have been identified and the trigger of severe symptoms has so far remained elusive.

However, a study recently published in Science Translational Medicine has identified driver genes for critical COVID-19 cases in young patients which could potentially serve as a target for new therapies for COVID-19.

The study was conducted on a young cohort of COVID-19 patients with severe symptoms who had comorbidities ruled out. The researchers conducted a multi-omics analysis and used an artificial intelligence system to identify genetic patterns that could help to explain why some younger individuals developed severe or life-threatening symptoms when the majority of individuals in that age range only had mild symptoms if any at all.

The study was conducted by researchers at the Human Molecular Immunogenetics Group at the University of Strasbourg on 72 patients under 50 years of age who had been hospitalized with COVID-19, 47 of whom were critical and on mechanical ventilation, 25 were noncritical patients on a COVID-19 ward, and 22 healthy individuals were in a control group.

The researchers performed whole-genome sequencing, whole-blood RNA sequencing, cytokine profiling, plasma/blood mononuclear cells proteomics, and high-throughput immunophenotyping. All the critically ill patients had exacerbated inflammation, increased coagulation, perturbed lymphoid and myeloid compartments, and viral cell biology, with one of the key features of the critically ill patients determined to be upregulated expression of the metalloprotease ADAM9.

The researchers also identified this genetic signature in a second cohort of 81 critically ill COVID-19 patients and 73 cases where patients had recovered, with the findings confirmed at the transcriptional and protein level as well as by proteolytic activity.

The researchers then silenced ADAM9 in human lung epithelial cells infected with SARS-CoV-19 and replication of the virus slowed, indicating ADAM9 is a driver of disease severity. ADAM9 antibodies or other approaches to reduce ADAM9 concentrations could potentially serve as a new treatment in serious cases of COVID-19.

You can read more about the research in the paper – Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort – which was recently published in Science Translational Medicine. DOI: 10.1126/scitranslmed.abj7521