Gene affects severity of respiratory disease

A specific gene's activity is directly correlated with respiratory infection severity, new research shows.

The gene in question is responsible for an enzyme – oleoyl-acyl-carrier-protein hydrolase (OLAH) – involved in the production of fatty acids. OLAH can produce fatty acids of varying carbon chain lengths but is particularly effective at catalysing oleic acid. Fatty acids play many key roles within the body, such as in forming the cell membrane and in how cells communicate with one another.

'Our first "aha" moment occurred during our analysis of patients hospitalised with A(H7N9) influenza [bird flu], where we discovered a consistent association between high expression levels of OLAH and fatal outcomes. Conversely, patients who recovered exhibited very low OLAH expression throughout their hospital stay' said Dr Brendon Chua, a viral and translational immunologist at the Doherty Institute, within the University of Melbourne, Australia, and study's co-corresponding author.

The upregulation of the gene was identified in patients who had severe infection with one of several different respiratory diseases, some of whom later died of their infection. These infections include the SARS-CoV-2 virus – which causes COVID-19, seasonal influenza virus and respiratory syncytial virus. The researchers also found elevated levels in children with multisystem inflammatory syndrome – which is associated with COVID-19.

The study, published in Cell, was founded on work by lead author Professor Katherine Kedzierska, head of the human T cell laboratory at the Doherty Institute, who discovered that during the 2013 bird flu outbreak in China, the OLAH gene upregulation was over 82 times greater in people who died compared to those who survived.

To further investigate the influence of OLAH levels on respiratory infection severity, a group of mice infected with influenza had their OLAH gene suppressed, resulting in a lower mortality rate (seven percent) compared to mice with unaltered OLAH gene expression (50 percent).

Higher levels of OLAH are believed to lead to the increased formation of lipid droplets in the blood, potentially causing a fatal condition known as a cytokine storm. Additionally, OLAH might aid viruses in replicating, as fatty acids provide an energy source for viral molecules.

'It took years of working closely with basic scientists and clinicians, from across the world, all studying different infections and diseases, for OLAH's important role in immune response to come to light. This is just the beginning of our exploration of OLAH; there is a lot more work to be done in infectious disease and other potential applications' said Dr Jeremy Chase Crawford from the department of host-microbe interactions at St Jude Children's Research Hospital, Memphis, Tennessee, and co-first author of the study.

Some believe that the correlation between OLAH and infection severity suggests the possibility of identifying potential cases of severe infections by testing a patient's OLAH levels and exploring potential treatment options using drugs that lower the level of the enzyme.