Salmonellosis continues to be a major Public Health concern. The pathogenicity of Salmonella enterica requires the activity of two type III protein secretion systems (T3SS) encoded within its pathogenicity islands 1 and 2. These T3SSs direct the translocation into host cells of a battery of bacterial effector proteins, which working in conjunction with one another, modulate a variety of cellular processes including actin cytoskeleton dynamics, gene expression, vesicle trafficking, and programmed cell death. Modulation of these cellular activities allows Salmonella to gain access to and replicate within host cells, avoid host defense mechanisms, induce intestinal inflammation, and/or reach deeper tissues. Over the years, work in our laboratory supported by this Grant has focused on the study of the cell biology of the complex functional interface between Salmonella enterica serovar Typhimurium (S. Typhimurium) and its host cells shaped by the activities of T3SS effector proteins. During the last funding period we have made significant progress in the understanding of the structure and function of several Salmonella T3SS effector proteins, as well as on the cellular responses that they elicit. Despite this progress, the biochemical activities and/or cellular targets of the majority of these effector proteins remain uncharacterized. During the next funding period we plan to use a multidisciplinary approach to study S. Typhimurium effector proteins, identified their cellular targets and examine their contribution to the host/pathogen interactions.

Public Health Relevance

Salmonellosis continues to be a very significant global Public Health concern. In the US alone there are an estimated 1 million cases of Salmonella infection every year resulting in an annual economic burden of $2.8 billion. World-wide, Salmonella infections result in more than 200,000 annual deaths, mostly children in developing countries. There are no effective vaccines to protect against these infections. The studies proposed in this Grant application may serve as the foundation for novel therapeutic and prevention strategies against Salmonella infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI055472-20A1
Application #
8578178
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
1995-05-01
Project End
2018-04-30
Budget Start
2013-05-16
Budget End
2014-04-30
Support Year
20
Fiscal Year
2013
Total Cost
$463,916
Indirect Cost
$185,148
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kohler, Amanda C; Spanò, Stefania; Galán, Jorge E et al. (2014) Structural and enzymatic characterization of a host-specificity determinant from Salmonella. Acta Crystallogr D Biol Crystallogr 70:384-91
Galán, Jorge E; Lara-Tejero, Maria; Marlovits, Thomas C et al. (2014) Bacterial type III secretion systems: specialized nanomachines for protein delivery into target cells. Annu Rev Microbiol 68:415-38
Hicks, Stuart W; Galan, Jorge E (2013) Exploitation of eukaryotic subcellular targeting mechanisms by bacterial effectors. Nat Rev Microbiol 11:316-26
Hannemann, Sebastian; Gao, Beile; Galan, Jorge E (2013) Salmonella modulation of host cell gene expression promotes its intracellular growth. PLoS Pathog 9:e1003668
Hicks, Stuart W; Charron, Guillaume; Hang, Howard C et al. (2011) Subcellular targeting of Salmonella virulence proteins by host-mediated S-palmitoylation. Cell Host Microbe 10:9-20
Spano, Stefania; Liu, Xiaoyun; Galan, Jorge E (2011) Proteolytic targeting of Rab29 by an effector protein distinguishes the intracellular compartments of human-adapted and broad-host Salmonella. Proc Natl Acad Sci U S A 108:18418-23
Hicks, Stuart W; Galan, Jorge E (2010) Hijacking the host ubiquitin pathway: structural strategies of bacterial E3 ubiquitin ligases. Curr Opin Microbiol 13:41-6
Galan, Jorge E (2009) Common themes in the design and function of bacterial effectors. Cell Host Microbe 5:571-9
Patel, Jayesh C; Hueffer, Karsten; Lam, Tukiet T et al. (2009) Diversification of a Salmonella virulence protein function by ubiquitin-dependent differential localization. Cell 137:283-94
Du, Fangyong; Galan, Jorge E (2009) Selective inhibition of type III secretion activated signaling by the Salmonella effector AvrA. PLoS Pathog 5:e1000595

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