The Pivotal Role of cGAS in Host Defense Against Mycobacterium Tuberculosis and in Particle-Induced Immunity

Date

2017-11-02

Authors

Cai, Haocheng

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Abstract

The cGAS-cGAMP-STING pathway is a major DNA sensing pathway in the cytosol. The DNA sensing mechanism is crucial for host defense against bacteria, viruses, and parasites. In the previous study from our lab, the cGAS-STING pathway has been identified as being critical for antiviral activities. However, anti-bacterial activity is more complicated due to the complexity of the invading agents. Mycobacterium tuberculosis (Mtb) is a pandemic pathogen that triggers millions of deaths every year. It is discovered that Mtb ejects its DNA component into host cytosol. We have uncovered the cGAS pathway, which elicits type I interferons and autophagy in macrophages and other cell types, as a defending mechanism against Mtb infection. cGAS is critical for mouse survival against chronic Mtb infection. In conclusion, cGAS is critical for the host defense against Mtb, especially in the induction of type I interferon and autophagy. Previous studies revealed that some fusogenic liposomes and enveloped virus-like particles can activate type I interferons. Here we have shown that fusogenic liposomes and nonenveloped virus-like particles can activate the cGAS pathway and trigger interferon production, which is associated with the amount of cytosolic DNA. Moreover, cGAS and STING are critical for the humoral immune response elicited by virus-like particles. Overall, we have delineated the significant role of cGAS in mediating the immune response induced by fusogenic liposomes and virus-like particles. Additionally, we have proven that cGAS heterozygous mice have largely retained the antiviral activity in herpes simplex virus infection, compared with wildtype mice. This has shed light on the development of cGAS inhibition therapies against autoimmune diseases. Overall, this dissertation has identified the pivotal roles of the cGAS-STING DNA sensing pathway in Mycobacterium tuberculosis infection and particle-induced immunity, as well as the effect of cGAS heterozygosity on antiviral activities.

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