Intestinal enterocolitis caused by food borne pathogens is a substantial health burden in the United States and internationally. Certain disease causing pathogens establish themselves within the host cells because they have evolved sophisticated mechanisms to evade host innate immunity. For example, pathogens secrete preformed effector proteins that influence innate immune and apoptotic signaling pathways thus inhibiting cytokine production, neutrophil recruitment, and/or activation of apoptosis. One group of bacterial effector proteins which usurp innate immune signaling is the AvrA-like family. These soluble proteins have potent inhibitory effects on the activation of the MARK and NF-kB signaling pathways, thereby modulating host inflammatory and apoptotic responses. This biochemical family is represented in multiple enteric pathogens including Salmonella, Yersinia, Vibrio and Aeromonas. We propose to 1) characterize the inhibitory profile of each AvrA-like protein using the Drosophila, a powerful genetic model which has functionally conserved innate immune and apoptotic pathways with mammals. We hypothesize that targeted blockade of distinct components of innate immune and apoptotic signaling controls differential effects on inflammatory or apoptotic outcomes in the whole organism. 2) We also propose to model the effects of AvrA-like proteins by their direct expression in the Drosophila gut epithelium, and in Drosophila hemocytes (which are analogous to human phagocytes) during pathogenic infection. We hypothesize that AvrA-like protein mediated inhibition of innate immune pathways localized to barrier epithelia or phagocytes facilitates pathogenic processes and untimely mediates the pathogenic outcome of infection by bacteria that secrete the particular AvrA-like protein. 3) Finally, we propose to use phenotypes resulting from the expression of AvrA-like proteins in Drosophila in a forward genetic screen for the discovery of novel innate immune and apoptotic regulatory genes. Together, these studies will further advance the understanding of the evasion strategies developed by enteric pathogens to escape the host immune response, and will contribute to our understanding of many intestinal inflammatory disorders. The candidate is committed to a career in biomedical research and his ultimate goal is to become an independent principal investigator in an academic setting. The rich environment provided by the support of his mentor, Dr Andrew Neish, M.D., his consultant Dr Kenneth Moberg, and a panel of eminent advisory scientists at Emory will provide the resources necessary to achieve his objectives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK081481-03
Application #
7858143
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-07-10
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$117,735
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Jones, Rheinallt M; Luo, Liping; Ardita, Courtney S et al. (2013) Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. EMBO J 32:3017-28
Wu, Huixia; Jones, Rheinallt M; Neish, Andrew S (2012) The Salmonella effector AvrA mediates bacterial intracellular survival during infection in vivo. Cell Microbiol 14:28-39
Jones, R M; Mercante, J W; Neish, A S (2012) Reactive oxygen production induced by the gut microbiota: pharmacotherapeutic implications. Curr Med Chem 19:1519-29
Jones, Rheinallt M; Luo, Liping; Moberg, Kenneth H (2012) Aeromonas salmonicida-secreted protein AopP is a potent inducer of apoptosis in a mammalian and a Drosophila model. Cell Microbiol 14:274-85
Wentworth, Christy C; Alam, Ashfaqul; Jones, Rheinallt M et al. (2011) Enteric commensal bacteria induce extracellular signal-regulated kinase pathway signaling via formyl peptide receptor-dependent redox modulation of dual specific phosphatase 3. J Biol Chem 286:38448-55
Wentworth, Christy C; Jones, Rheinallt M; Kwon, Young Man et al. (2010) Commensal-epithelial signaling mediated via formyl peptide receptors. Am J Pathol 177:2782-90
Royan, Sandhya V; Jones, Rheinallt M; Koutsouris, Athanasia et al. (2010) Enteropathogenic E. coli non-LEE encoded effectors NleH1 and NleH2 attenuate NF-ýýB activation. Mol Microbiol 78:1232-45