Oxidised Cholesterols in the Lung: Novel Immune Regulators during Bacterial and Viral Respiratory Infections

Abstract

My laboratory discovered that oxidised cholesterols, so called oxysterols, are produced in the lung in response to both bacterial (M. tuberculosis) and viral respiratory infections (influenza, SARS-CoV-2) through upregulation of the oxysterol producing enzymes CH25H and CYP7B1. I will share with you our data demonstrating that these oxysterols facilitate the chemotactic recruitment of immune cells expressing the oxysterol-sensing receptor GPR183 to lung. While GPR183 is essential for early infiltration of macrophages to the site of infection, it is not required for migration of neutrophils, T or B cells. Both mice deficient in GPR183 and WT mice treated with a GPR183 antagonist have reduced macrophage infiltration into the lungs after influenza A virus and SARS-CoV-2 infection which results in reduced production of inflammatory cytokines. Importantly, SARS-CoV-2 infected animals treated with the GPR183 antagonist were clinically less ill and had lower viral loads compared to vehicle treated animals. Our work demonstrates an important role for oxysterols during infections in the lung and provides the first preclinical evidence for the benefits of inhibiting GPR183 activity to reduce severity of viral respiratory infections.

Biography

Associate Professor Katharina Ronacher graduated with an MSc degree (cum laude) in Medical Biochemistry from the University of Vienna, Austria, and was subsequently awarded a prestigious scholarship from the Austrian Ministry of Science and Technology to complete her PhD at the University of Cape Town, South Africa. After her post-doctoral studies at Stellenbosch University she was offered a faculty position and was Senior Scientist on several large clinical research trials funded by the Bill and Melinda Gates Foundation, the European Union and the US National Institutes of Health. (NIH). In 2015, she was awarded an NIH R01 grant as CIA (US$ 1.75 million) for her ground-breaking research into the underlying immunological and metabolic mechanisms of increased susceptibility of diabetes patients to tuberculosis. With this grant she has lead the international ALERT Consortium with clinical field sites in South Africa and at the Texas/Mexico border.

In 2017, she relocated to Brisbane to lead the Infection, Immunity and Metabolism laboratory at Mater Research-UQ, but continues to collaborate with clinicians and researchers in South Africa, the USA and Europe.