High cholesterol has historically been linked to an increased risk of heart disease. But can high cholesterol be protective against infections?
Associate Professor Katharina Ronacher and post-doctoral research fellow Dr Stacey Bartlett celebrated success recently by having their research GPR183 regulates interferons, autophagy and bacterial growth during Mycobacterium tuberculosis infection and is associated with TB disease severity published in Frontiers in Immunology, the leading peer-review journal in the field.
One of the first studies of its kind, Mater Researcher Associate Professor Ronacher’s work shows that a receptor for oxidised cholesterol is important for the immune regulation of infections.
Cholesterol is oxidised in the body to facilitate its elimination and it was only recently discovered that these oxidised cholesterol molecules play a role in immune function.
“We originally identified that receptor in patients who suffer from both diabetes and tuberculosis. Individuals who had lower expression of this receptor in their blood had more severe disease on chest x-rays,” Dr Ronacher said.
“This identified the link between this cholesterol receptor and the lung disease severity.”
An added surprise finding—whose results are yet to be published—occurred when Dr Ronacher and her team took blood from patients with high cholesterol or high blood sugar and added bacteria. Blood immune cells from people with high cholesterol were more able to contain the bacterial growth, whereas those with high glucose in their blood allowed for easier replication for the bacteria to occur.
“This finding shows that in a way, high cholesterol can be protective.”
From her breakthrough work done at the Translational Research Institute labs, shows that this receptor controls the replication of bacteria inside the macrophages (immune cells) and when the receptor is activated with a natural oxidised cholesterol the macrophages can be encouraged to commence a process called autophagy which reduces the growth of bacteria inside of the cells, even in the absence of antibiotics.
“The natural oxidised cholesterol has a short half-life and gets degraded fairly rapidly in the body. Therefore, we are currently engaging with industry partners in order to develop synthetic cholesterols with better efficacy and bioavailability. We will then test these synthetic cholesterols to control in the intracellular replication of bacteria, either alone or with antibiotics, to improve treatment outcomes.”
Traditionally bacterial infections are treated with antibiotics, but the rise in antibiotic resistant strains requires novel and innovative treatment approaches. The hope is that by targeting the host immune cells to better fight the infection in addition to giving conventional antibiotics improved treatment outcomes for both drug-sensitive and drug-resistant infections can be achieved. This would also lead to shorter treatment duration and increase patients’ adherence to the treatment.
“We have also made the exciting discovery that this receptor plays a role in viral infections, including Respiratory syncytial virus (RSV), influenza and more recently COVID-19. We are now beginning conducting research whether targeting this receptor is beneficial to regulate inflammatory markers during viral infections in addition to controlling intracellular bacterial growth.”
This work involved collaborators at The University of Queensland and international scientists from Denmark, South Africa and the United States of America. The work was funded by the US National Institutes of Health, the European Union, the Australian Respiratory Council, the Australian Infectious Disease Research Centre and the Mater Foundation.