The early detection of microbes is the responsibility of the innate immune system which has evolved to sense pathogen derived molecules such as lipopolysaccharides and non-self nucleic acid, to trigger host defense countermeasures. These sensors include the RIG-I-like helicase (RLH) family that specifically recognizes viral RNA, as well as the cytoplasmic, nucleotide binding oligermerization domain (NOD)-like receptor and Toll-like receptor (TLR) pathways that sense a variety of microbial derived molecules. Comprehending how the cell senses foreign DNA, generated by certain viruses, bacteria and possibly parasites has proven elusive but is of significant importance since such information could shed insight into the causes of microbial related disease, including viral associated cancers and autoimmune disorders. Plasmacytoid dendritic cells are known to utilize TLR9 to detect pathogen-associated DNA and to trigger the production of type I interferon (IFN), as well as other cytokines, although alternate key DNA detecting sensors remain to be identified. Recently however, a molecule referred to as AIM2 (absent in melanoma 2) was found to be essential for mediating inflammatory reactions triggered by cytoplasmic DNA. In addition, an endoplasmic reticulum associated protein referred to as STING (for stimulator of interferon genes) was demonstrated as being pivotal for facilitating IFN production in response to intracellular DNA and a variety of DNA pathogens. Here, we review recent discoveries relating to the detection of foreign DNA, including the importance of the STING and AIM2 and the activation of innate signaling pathways.
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