STING signaling and host defense against microbial infection

Abstract

The first line of host defense against infectious agents involves activation of innate immune signaling pathways that recognize specific pathogen-associated molecular patterns (PAMPs). Key triggers of innate immune signaling are now known to include microbial-specific nucleic acid, which is rapidly detected in the cytosol of the cell. For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defense molecules and cytokines that stimulate adaptive immune responses. In addition, host defense countermeasures, including the production of type I interferons (IFNs), can also be triggered by microbial DNA from bacteria, viruses and perhaps parasites and are regulated by the cytosolic sensor, stimulator of interferon genes (STING). STING-dependent signaling is initiated by cyclic dinucleotides (CDNs) generated by intracellular bacteria following infection. CDNs can also be synthesized by a cellular synthase, cGAS, following interaction with invasive cytosolic self-DNA or microbial DNA species. The importance of STING signaling in host defense is evident since numerous pathogens have developed strategies to prevent STING function. Here, we review the relevance of STING-controlled innate immune signaling in host defense against pathogen invasion, including microbial endeavors to subvert this critical process.

Immunity: Fighting infection with a STING

In response to microbial infections a protein sensor named stimulator of interferon genes (STING) initiates the production of small defensive proteins called interferons. This is an early and ‘innate’ immune response, that is, one not targeted at specific invaders. Jeonghyun Ahn and Glen Barber at the University of Miami, USA, review the relevance of STING signaling in defense against infection, including consideration of microbial activities that can help the microbes evade this immune response. STING signaling is initiated by the presence of fragments of microbial genetic material called cyclic dinucleotides. These can be derived via cyclic GMP-AMP synthase (cGAS) from the DNA of invading viruses, bacteria or larger parasites such as single-cell protozoans. Discoveries revealing the significance and mechanism of our STING signaling system could lead to new strategies for combating infections, using either drugs or vaccines.