Epithelial cells act as the most proximal arm of the innate immune system by sensing bacterial products and recruiting neutrophils to mucosal surfaces. During colonization, these cells are concurrently exposed to a vast array of microbial products, and it is not well understood how these combinations may alter the responses of epithelial cells. Preliminary data presented here describe a novel system for the generation of inflammation in the setting of polymicrobial stimulation. Concurrent exposure to two important human respiratory pathogens, S. pneumoniae and H. influenzae, induces synergistic production of proinflammatory cytokines by epithelial cells. This effect occurs both in vitro and in vivo and is associated with neutrophil recruitment. This proposal is designed to characterize the mechanism of this response. The first specific aim will address the hypothesis that specific bacterial components from S. pneumoniae and H. influenzae are necessary and sufficient for synergistic induction of inflammation. The second specific aim addresses specific host molecular mechanisms involved in this pathway. These studies have the potential to further the current understanding of immune responses at colonized mucosal surfaces, with implications for both colonization and invasive disease. ? ? This application describes a program designed to provide Dr. Adam Ratner with the skills necessary to become an independent investigator in microbial pathogenesis. Dr. Ratner has completed fellowship training in pediatric infectious diseases and will be mentored by Dr. Jeffrey Weiser, an expert in the pathogenesis of respiratory diseases. The program includes didactic study in the areas of genetics, immunology, and bacterial pathogenesis. In addition, an in-depth laboratory experience will expose Dr. Ratner to a wide variety of techniques in the areas of cell biology, biochemistry, physiology, and molecular biology, thus providing a solid foundation for beginning an independent research career. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AI065450-01
Application #
6955295
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Lambert, Linda C
Project Start
2005-06-15
Project End
2009-04-30
Budget Start
2005-06-15
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$117,072
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shah, Samir S; Wood, Sarah M; Luan, Xiquan et al. (2010) Decline in varicella-related ambulatory visits and hospitalizations in the United States since routine immunization against varicella. Pediatr Infect Dis J 29:199-204
Randis, Tara M; Kulkarni, Ritwij; Aguilar, Jorge L et al. (2009) Antibody-based detection and inhibition of vaginolysin, the Gardnerella vaginalis cytolysin. PLoS One 4:e5207
Wood, Sarah M; Shah, Samir S; Bafana, Margaret et al. (2009) Epidemiology of methicillin-resistant Staphylococcus aureus bacteremia in Gaborone, Botswana. Infect Control Hosp Epidemiol 30:782-5
Aguilar, Jorge L; Kulkarni, Ritwij; Randis, Tara M et al. (2009) Phosphatase-dependent regulation of epithelial mitogen-activated protein kinase responses to toxin-induced membrane pores. PLoS One 4:e8076
Gelber, Shari E; Aguilar, Jorge L; Lewis, Kanako L T et al. (2008) Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis. J Bacteriol 190:3896-903
Ratner, Adam J; Aguilar, Jorge L; Shchepetov, Mikhail et al. (2007) Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Cell Microbiol 9:1343-51
Antunes, Marcelo B; Woodworth, Bradford A; Bhargave, Geeta et al. (2007) Murine nasal septa for respiratory epithelial air-liquid interface cultures. Biotechniques 43:195-6, 198, 200 passim
Lysenko, Elena S; Clarke, Thomas B; Shchepetov, Mikhail et al. (2007) Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing. PLoS Pathog 3:e118
Ratner, Adam J; Hippe, Karen R; Aguilar, Jorge L et al. (2006) Epithelial cells are sensitive detectors of bacterial pore-forming toxins. J Biol Chem 281:12994-8
Shah, Samir S; Ratner, Adam J (2006) Trends in invasive pneumococcal disease-associated hospitalizations. Clin Infect Dis 42:e1-5

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