Listeria monocytogenes is a gram-positive, opportunistic, intracellular bacterial pathogen that causes food borne illness. Given its well-characterized infection cycle and genetic amenability, L. monocytogenes provides a powerful tool to interrogate the fundamental aspects of intracellular bacterial pathogenesis and the host immune response to invasion by intracellular pathogens. It has previously been demonstrated that L. monocytogenes that enter into the host cell cytosol secrete a signaling nucleotide, c-di-AMP, resulting in stimulation of host IFN-? production. Our preliminary studies have uncovered important roles for c-di-AMP signaling in the ability of the bacterium to grow in broth and within the host. Furthermore, evidence suggests c- di-AMP may have functional consequences beyond IFN-? induction by the infected host cell. Using proteomics and genetic studies we have identified novel bacterial and host pathways that may mediate the numerous phenotypes associated with this unique bacterial signaling molecule.
In Aim I, we propose to explore the role of c-di-AMP in the generation of a stable bacterial cell and the effects of this on the host immune response and bacterial resistance to antibiotics.
In Aim II, we will define the role for c-di-AMP mediated adaptation to intracellular nutrients. In the final aim, we will characterize the effects of c-di-AMP binding to a novel host protein and elucidate the effects of these interactions on the outcome of infection. Together these studies will define the molecular mechanisms of c-di-AMP signaling that mediate host pathogen interactions during infection by this intracellular bacterium.
Intracellular pathogens remain on of the largest human health burdens in the 21st century. By characterizing the mechanism of host-pathogen interactions using the model intracellular bacterium L. monocytogenes we will define the fundamental mechanisms employed by intracellular pathogens to promote disease and the host response to these infections.
|Huynh, TuAnh Ngoc; Woodward, Joshua J (2016) Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm. Curr Opin Microbiol 30:22-9|
|Huynh, TuAnh Ngoc; Luo, Shukun; Pensinger, Daniel et al. (2015) An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc Natl Acad Sci U S A 112:E747-56|
|Choi, Philip H; Sureka, Kamakshi; Woodward, Joshua J et al. (2015) Molecular basis for the recognition of cyclic-di-AMP by PstA, a PII-like signal transduction protein. Microbiologyopen 4:361-74|