Unveiling the Roles of Metabolism and Genetics
Unravelling the mysteries behind why individuals develop asymptomatic or mild disease while others suffer from severe or even fatal diseases is challenging. Factors such as age, sex, ethnicities and underlying health conditions have long been recognized as key determinants of disease outcome. In the fight against respiratory viruses, understanding pathways involved in metabolism contributing to the outcome of disease has emerged as a crucial frontier.
Prof. Katherine Kedzierska (University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia) and her team have made an intriguing discovery related to the disease severity in patients suffering from H7N9 virus infection. Through a transcriptomics approach by comparing gene profiles early and late after hospital admission in patients who succumb to infection compared to survivors, they identified an enzyme known as oleoyl-ACP-hydrolase, a player in fatty acid metabolism, as a pivotal mediator of severe disease in H7N9 patients. The team showed a strong link between elevated expression of this enzyme and increased disease severity. To further characterise this finding, knock-out mice were generated and challenged with H3N2 virus. These animals displayed less severe disease, milder clinical symptoms, lower viral titers in their lungs, and reduced lipid droplets compared to inoculated wild type mice. This insight sheds new light into metabolic enzymes contributing to the development of severe disease during influenza A virus infections.
On another front in the battle against infectious diseases, male sex has emerged as a significant risk factor for developing severe COVID-19. Dr. Sebastian Beck and his colleagues (Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany) have unveiled a genetic variant that increased the enzymatic activity of CYP19A1, a testosterone-to-estradiol metabolizing enzyme, in male patients suffering from severe COVID-19. This heightened CYP19A1 activity in the lungs has been linked to disruptions in sex hormone levels and impaired lung function in male hamsters infected with SARS-CoV-2. A clinically approved inhibitor of CYP19A1, known as letrozole, improved improved lung function and restored the dysregulated sex hormones specifically in SARS-CoV-2 inoculated male hamsters. This discovery may hold the key as a novel mitigating strategy for severe COVID-19 in male patients. Intriguingly, SARS-CoV-2 is not the only virus hitting the hypothalamic-pituitary gonadal axis and similar results were also obtained for patients suffering from severe influenza A virus infection.
As the pursuit of knowledge in the field of infectious diseases advances, these revelations about the interplay between metabolism and genetics offer new hope for understanding molecular mechanisms responsible for the disease outcome and could ultimately lead to combating severe viral infections.
