Salmonellosis continues to be a major world-wide health problem. Although Salmonella infections (other than typhoid fever) are usually self limiting, in immunocompromised individuals (e.g. elderly and AIDS patients) non- typhoid Salmonella can cause life threatening disease. S. typhi infections remain a very series problem in third world countries, particularly in children under the age of three. An essential pathogenic feature of all Salmonella spp. is their ability to gain access to mammalian cells that are normally non-phagocytic. The internalization process is the result of an intimate interaction between the bacteria and the host cell which results in the induction of signal transduction pathways that lead to membrane ruffling and bacterial internalization. Another feature of Salmonella infections is that the pathology of this disease is largely due to the host response to the invading pathogen. Little is known about the mechanisms by which Salmonella induces host responses but it is our hypothesis that signal transduction pathways evoked by Salmonella at the host cell surface may lead to the activation of transcription factors with subsequent production of biologically active molecules (e.g. cytokines, eicosenoids). These molecules may in turn modulate both the inflammatory as well as the immune response of the host to these organisms. Recent work from our laboratory has begun to outline the signaling pathways evoked by Salmonella in host mammalian cells. However, mere work is needed to better defined those pathways as well as to understand the Salmonella-induced host cellular mechanisms that lad to the activation of transcription factors. it is an objective of this research project to use a variety of genetic, biochemical and cell biological techniques to define more precisely the host cell signal transduction pathways evoked by Salmonella resulting in bacterial uptake. In addition, we intend to identify nuclear responses evoked by Salmonella that may lead to the activation of transcription factors and subsequent production of modulators of the inflammatory or immune responses. Although we will initially use S. typhimurium in our experiments, the results obtained are likely to be extrapolatable to all Salmonella serotypes and may help to define new concepts around which new drugs can be designed that may help to prevent infections by Salmonella or other intracellular pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM052543-05
Application #
2881571
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1995-05-01
Project End
1999-04-30
Budget Start
1998-09-01
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Haghjoo, Erik; Galan, Jorge E (2004) Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proc Natl Acad Sci U S A 101:4614-9
Hernandez, Lorraine D; Pypaert, Marc; Flavell, Richard A et al. (2003) A Salmonella protein causes macrophage cell death by inducing autophagy. J Cell Biol 163:1123-31
Kubori, Tomoko; Galan, Jorge E (2003) Temporal regulation of salmonella virulence effector function by proteasome-dependent protein degradation. Cell 115:333-42
Carlyon, Jason A; Chan, Wai-Tsing; Galan, Jorge et al. (2002) Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to the inhibition of superoxide production and bacterial proliferation. J Immunol 169:7009-18
Murli, S; Watson, R O; Galan, J E (2001) Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells. Cell Microbiol 3:795-810
Galan, J E (2001) Salmonella interactions with host cells: type III secretion at work. Annu Rev Cell Dev Biol 17:53-86
Zhou, D; Chen, L M; Hernandez, L et al. (2001) A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. Mol Microbiol 39:248-59
Galan, J E; Zhou, D (2000) Striking a balance: modulation of the actin cytoskeleton by Salmonella. Proc Natl Acad Sci U S A 97:8754-61
Galan, J E; Fu, Y (2000) Modulation of actin cytoskeleton by Salmonella GTPase activating protein SptP. Methods Enzymol 325:496-504
Mitra, K; Zhou, D; Galan, J E (2000) Biophysical characterization of SipA, an actin-binding protein from Salmonella enterica. FEBS Lett 482:81-4

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