Listeria monocytogenes
Listeria monocytogenes (Lm) is a gram-positive intracellular, food-borne human pathogen and an important public health problem. Because Lm is genetically tractable, has a well-characterized infection cycle, and has in vitro and in vivo models of infection, it is an ideal organism to study the fundamental aspects of intracellular pathogenesis and the host innate immune response to cytosolic invasion.
Cellular infection by Lm results in bacterial entry into the cytoplasm of the host cell followed by replication of the bacteria. Lm hijacks host cell actin as a means of generating bacterial motility, which allows bacterial translocation into neighboring cells without the need of leaving the confines of the intracellular niche. How Lm adapts to the nutrients of the cytosol and efficiently counteracts/evades the host cell-intrinsic mechanisms of bacterial clearance are central to the investigation of the Woodward lab.
Staphylococcus aureus
Staphylococcus aureus is a gram-positive opportunistic pathogen responsible for a variety of chronic and acute infections. Continued emergence of S. aureus antimicrobial resistance has garnered this pathogen significant notoriety and a desperate need for new therapeutic interventions. While mobile genetic elements confer resistance to cell wall targeting antibiotics, the emergence of drug resistant small colony variants (SCVs) is also common during S. aureus infection. SCVs have specific mutations in central metabolic pathways (heme, thymidine, etc.) that render them drug resistant. We are actively engaged in exploring phenotypic and virulence traits of distinct SCV genotypes and the impacts of their presence in both the cystic fibrosis lung and chronic wound infections.
L. monocytogenes infecting murine hepatocytes and spreading by actin based motility.
A L. monocytogenes focus of infection in a monolayer of murine hepatocytes. Actin and DNA.
Cyclic di-AMP
Cyclic di-adenosine monophosphate (c-di-AMP) has recently emerged as a broadly conserved second messenger of fundamental importance for microbial growth and physiology. C-di-AMP is synthesized from two molecules of ATP by di-adenylate cyclases (DACs). The signal is degraded by DHH/DHHA1 and HD domain phosphodiesterases or secreted by MDR transporters. Second messengers initiate signal transduction by binding to and altering protein function. We identified several c-di-AMP binding proteins that are broadly conserved in numerous bacterial species and are actively defining the biological functions and the molecular details of these interactions.
PUBLICATIONS
McFarland, AP, Woodward, JJ Flying Under the Radar: Immune Evasion by Group B Streptococcus. Cell Host and Microbe. 2016, 20 (1): 4-6.
Huynh, T.N., Choi, P., Sureka, K., Ledvina, H.E., Campillo, J., Tong, L.*, Woodward, J.J.* Cyclic di-AMP targets the cystathionine beta-synthase domain of the osmolyte transporter OpuC. Mol Microbiol. 2016 Jul 5.
Camargo AC, Woodward JJ, Nero LA. The Continuous Challenge of Characterizing the Foodborne Pathogen Listeria monocytogenes. Foodborne Pathog Dis. 2016 Apr 27.
Huynh TN, Woodward JJ. Too Much of a Good Thing: Regulated depletion of c-di-AMP in the bacterial cytoplasm. Current Opinion in Microbiology. April 2016: Vol. 30, 22-29.
Choi, P.H., Sureka, K., Woodward, J.J.*, Tong, L.* Molecular basis for the recognition of cyclic-di-AMP by PstA, a PII-like signal transduction protein. Microbiologyopen. 2015
Huynh, T.N., Luo, S., Pensinger, D., Sauer, J.D., Tong, L.*, Woodward, J.J.* An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc. Natl. Acad. Sci. USA. 2014.
Sureka, K., Choi, P.H., Precit, M., Delince, M., Pensinger, D., Huynh, T.N., Jurado, A.R., Goo, Y.A., Sadilek, M., Iavarone A.T., Sauer, J.D., Tong, L.*, Woodward, J.J.* The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell (2014). Volume 158, Issue 6, p1389–1401, 11 September 2014