The Genomes of 3,000 Dangerous Bacteria are Helping to Fight Antibiotic Resistance

Photo Credit: Ecole Polytechnique Federale De Laussane

Researchers from UT Southwestern have identified a mechanism believed to be the body’s first response to an infection. The mechanism, which was described in a new paper in Science, involves a DNA-sensing enzyme that forms tiny ‘bioreactor’ droplets when a patient becomes infected, which then produce molecules that stimulate innate immunity. This work may help us to develop novel treatment approaches to infections and autoimmune diseases.

In 2012, the lab behind this research uncovered an enzyme called cyclic GMP-AMP synthase (cGAS), which they identified as a sensory ‘alarm system’ that triggers innate immunity. This is the immune system that we develop in early development, as opposed to the adaptive immune system we obtain throughout our lives. The enzyme works by triggering an immune response when it encounters any DNA sequences in regions of the cell where DNA shouldn’t be, regardless of whether it is host or pathogenic DNA. The team also identified a small molecule known as cGAMP, which the enzyme produces to act as a secondary messenger signal.

Now, the pair of researchers, Zhijian ‘James’ Chen and Mingjian Du, have identified the mechanism by which cGAS reacts to pathogenic DNA. When the enzyme encounters genetic material, it binds with the DNA to form a membrane-less droplet microreactor.

“The droplets act as microreactors to speed up reactions that churn out the small molecule cGAMP, which activates the immune system,” said Dr Chen, co-author of the paper, Director of the Center for Inflammation Research, and a Member of the Center for the Genetics of Host Defense.

By experimenting with different quantities of the components, the pair found that both DNA and cGAS are needed in concentrations above a certain threshold for droplet formation to trigger. It is this threshold that allows cGAS to tolerate the small quantities of self-DNA that can circulate within the cell without activating the immune system. This may also explain how individuals with higher levels of self-DNA could develop auto-immune diseases, as the concentration of DNA has surpassed the necessary threshold.

“With a detailed understanding of the pathway, it will be possible to develop and design a variety of drugs for cancer and other diseases,” Dr Chen said. “Several companies are working on potential treatments now. For autoimmune diseases such as lupus – in which cGAS is aberrantly turned on by self-DNA in the cell’s interior – the goal is to find cGAS inhibitors. With infections, it would be good to enhance the body’s immune defence. There is also the hope of finding drugs that stimulate the cGAS pathway to boost the effects of cancer immunotherapy.”