Researchers at the University of Texas Southwestern Medical Center recently discovered the body’s innate immune sensor that recognizes DNA from the pathogen Mycobacterium tuberculosis, the pathogenic bacteria responsible for most cases of tuberculosis. The study was published in the journal Cell Host & Microbe and is entitled “Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis”.
Tuberculosis is a serious infectious disease with widespread global reach that typically attacks the lungs. It is the leading cause of bacteria-related death worldwide (approximately 1.5 million deaths annually) and it is estimated that around one-third of the world’s population is infected with the bacterium, although the disease is asymptomatic in the majority of the cases. Tuberculosis is characterized by a chronic cough with blood, fever, night sweats and weight loss, and can be spread by airborne contact with an infected individual. It is a disease mainly prevalent in underdeveloped countries, but it is estimated that approximately 12,000 to 15,000 cases arise in the United States every year. Antibiotic resistance is a growing issue in the fight against the disease and new therapies are urgently needed.
“Tuberculosis [TB] is already a significant global pandemic and the threat of multidrug resistance is high. If drug-resistant TB were to spread more internationally, then TB could become a real public health disaster,” noted the study’s co-senior author Dr. Michael Shiloh in a news release.
Cyclic GMP-AMP synthase (cGAS) is a DNA sensor of the body’s immune system that can induce the production of type I interferon, a key pathway that triggers the protective defenses of the immune system against infections. Researchers have now discovered that cGAS is the host sensor responsible for identifying M. tuberculosis DNA.
In the study, the research team showed that the detection of M. tuberculosis by cGAS induces the production of a compound called cyclic GMP-AMP (cGAMP). In turn, cGAMP triggers a signalling cascade that promotes interferon and inflammatory cytokine production, and activation of an important host-defense mechanism known as autophagy, a mechanism through which dysfunctional cellular components are degraded. Depletion of cGAS in human or mouse immune cells was found to inhibit cytokine production and autophagy induction. In addition, mice lacking cGAS were found to succumb much quicker in comparison to animals with normal cGAS activity when infected with M. tuberculosis.
“Based on this outcome, we believe that modulating cGAS activity could be a novel approach to therapy. There remains a dire need for new therapies against tuberculosis, and thus identifying pathways to stop the pathogen is of vital importance,” noted Dr. Shiloh.
“The finding that the cGAS pathway is important for sensing and defending against TB infection suggests that this pathway may be harnessed to develop better vaccines and therapeutics to protect people from this dreaded disease,” added the study’s co-senior author Dr. Zhijian “James” Chen, who discovered the cGAS enzyme in 2012 and its role in the immune responses to DNA.
The team concluded that cGAS is a crucial innate immune sensor of M. tuberculosis infection and that it has a strong potential in the development of immunity-based therapeutics against tuberculosis and perhaps even other infectious diseases.