Innate Immunity

Host immune sensing of cyclic dinucleotides during bacterial infection.

The innate immune system is comprised of germ-line encoded receptors that detect components of microbes. Cyclic dinucleotides have emerged as potent modulators of host inflammation and immunity. During cytosolic infiltration by bacterial pathogens, binding of bacterial cyclic dinucleotides to the host receptor STING results in the activation of a host interferon response. Additionally, during viral infection or cellular damage, cytosolic DNA is sensed by the host protein cGAS, resulting in production of cyclic AMP-GMP (cGAMP) which also results in STING activation. We recently identified a novel  cyclic dinucleotide binding protein RECON, which regulates host inflammation through NF-kB signaling specifically in response to bacterial nucleotides. Activation of these pathways has been implicated in host resistance to infection as well as autoinflammatory disorders. We are currently detailing the role of cyclic dinucleotide immune detection and its impacts on host signal transduction and infection outcome using tissue culture and murine models of infection.

PUBLICATIONS

Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE, Onia L, McWhirter SM, Katibah GE, Corn JE, Woodward JJ, Raulet DH. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. 2019 Sep;573(7774):434-438.

McFarland AP, Burke TP, Carletti AA, Glover RC, Tabakh H, Welch MD, Woodward JJ. RECON-Dependent Inflammation in Hepatocytes Enhances Listeria monocytogenes Cell-to-Cell Spread. mBio. 2018 Jul 5;9(3):e00526-18.

McFarland, AP, Woodward, JJ Flying Under the Radar: Immune Evasion by Group B Streptococcus. Cell Host and Microbe. 2016, 20 (1): 4-6.

Gray EE, Treuting PM, Woodward JJ, Stetson DB. Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutières Syndrome. J Immunol. 2015 Sep 1;195(5):1939-43.

 

Fu J, Kanne  DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, Mechette K, Leong JJ, Lauer P, Liu W, Sivick KE, Zeng Q, Soares KC, Zheng L, Portnoy DA, Woodward JJ, Pardoll DM, Dubensky Jr. TW, Kim Y. Science STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Translational Medicine  15 Apr 2015: 7 (283): 283

 

An J, Woodward JJ, Sasaki T, Minie, M., Elkon, K.B. J. Cutting Edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction. J Immunol. 2015 May 1;194(9):4089-93

Woodward JJ, Iavarone AT, Portnoy DA c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science. (2010) 328, 1703-5.

The Department of Microbiology

The University of Washington

© 2016 by Joshua Woodward.