Innate Immune Detection of Bacterial Nucleic Acids and Nucleotides

PI: Dr. Daniel Stetson

Department of Immunology
University of Washington, Seattle, WA

Innate immune detection of nucleic acids is an essential form of host defense against viruses and bacteria. In mammals, two key receptor systems are responsible for linking nucleic acid detection to the immune response. First, Toll-like receptors (TLRs) expressed by sentinel immune cells like dendritic cells and macrophages sample phagocytosed material for the presence of foreign nucleic acids. Second, broadly expressed intracellular sensors mediate detection of nucleic acids within the infected cell itself.

The RNA helicases RIG-I and MDA5 detect RNA and signal through the IPS-1 adaptor protein. In contrast, sensors that detect DNA from viruses and invasive bacteria remain incompletely defined, but signal through the STING adaptor protein. In addition, cyclic dinucleotides from bacteria trigger a potent, STING-dependent type I interferon response when introduced into the cytosol of infected cells.

We have found that DNA and cyclic dinucleotides trigger a common signaling pathway distinct from the pathway triggered by RNA. We have identified a family of thirteen murine candidate receptors that activate STING-dependent signaling. The goals of this grant are to

  • determine which intracellular signaling pathways are activated by key invasive gram negative bacteria
  • characterize the role of the candidate sensors in activation of IFNs by DNA and cyclic dinucleotides
  • establish the importance of these sensors and signaling pathways in the host-protective response to bacterial infection