The intestinal epithelia barrier and the mucosal immune system detect and respond to intestinal antigens. This response varies from tolerance to resident commensals an active immune response to pathogens. A better understanding of the interaction between intestinal microflora and the intestinal mucosa should provide insight into the pathogenesis of intestinal inflammation. The underlying hypotheses at work are 1) pathogens uniquely alter gene expression in the intestinal mucosa and specific receptors in the intestinal mucosa are responsible for initiating host cell responses 2) NF-kappaB activation functions as a nodal point for pathways activated by innate and adaptive immunity 3) In addition to eliciting transcriptional responses intestinal microbes induce dramatic changes in the actin cytoskeleton. The proposed research will focus on model systems familiar to our laboratory. As part of our preliminary studies for this proposal, we have established and tested an expression cloning strategy capable of identifying known and novel activators of pathogen responsive host transcription factors. To accomplish these goals, the specific aims of this proposal are:
Specific Aim I : To identify signaling molecules that contribute to the host cell NF-kappaB response to bacteria.
Specific Aim II : To delineate molecular pathways that mediate host cell actin cytoskeletal changes in response to bacteria. The long term goals of this research program is to identify proteins associated with and that influence immunity, inflammation and host resistance to intestinal inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062773-04
Application #
7657373
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Rothermel, Annette L
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$333,393
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Yassour, Moran; Vatanen, Tommi; Siljander, Heli et al. (2016) Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med 8:343ra81
Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank et al. (2014) Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 6:152-8
Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank et al. (2014) BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clin Immunol 155:213-9
de Luca, Antonella; Smeekens, Sanne P; Casagrande, Andrea et al. (2014) IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 111:3526-31
Smeekens, Sanne P; Ng, Aylwin; Kumar, Vinod et al. (2013) Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun 4:1342
Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank et al. (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109:17537-42
Quintin, Jessica; Saeed, Sadia; Martens, Joost H A et al. (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12:223-32
Conway, Kara L; Goel, Gautam; Sokol, Harry et al. (2012) p40phox expression regulates neutrophil recruitment and function during the resolution phase of intestinal inflammation. J Immunol 189:3631-40
Gewurz, Benjamin E; Towfic, Fadi; Mar, Jessica C et al. (2012) Genome-wide siRNA screen for mediators of NF-?B activation. Proc Natl Acad Sci U S A 109:2467-72
Jostins, Luke; Ripke, Stephan; Weersma, Rinse K et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119-24

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