The outermost part of Gram-negative bacteria is the lipopolysaccharide (i.e. LPS). This molecule constitutes a permeability barrier that protects bacteria from a variety of noxious agents, and it is recognized by the host innate immune system of different animals and targeted by several natural antimicrobial peptides. Many Gram-negative pathogens have evolved mechanisms to modify their LPS in ways that decrease recognition by the host and increase resistance to antimicrobial peptides and certain toxic metals. In Salmonella enterica, which is the etiologic agent of typhoid fever and gastroenteritis, many of these LPS modifications are observed only under conditions that activate the PmrA/PmrB regulatory system. This proposal describes experiments aimed at understanding how the activity of the PmrA/PmrB system is dynamically controlled in response to internal and external inputs. Our studies will focus on a novel gene that encodes both a small peptide and small RNA, and on a set of Salmonella-specific genes that are required for survival inside macrophages. In addition, we will analyze the distinct properties that the PmrD protein plays in Salmonella, where it functions to activate the PmrA protein, and in the related species Escherichia coli, where it lacks this ability. We will examine whether the ability of commensal E. coli to colonize the mouse intestine is compromised when E. coli carries out the PmrA-controlled LPS modifications under inducing conditions that promote such activation in Salmonella. An accomplishment of these goals will uncover how the PmrA/PmrB system - a major regulator of LPS modifications in enteric bacteria - controls the remodeling of its cell surface in ways that protect it from antimicrobial insult.

Public Health Relevance

Bacteria often modify their cell surface in ways that alter their resistance to antimicrobial agents. The proposed research will uncover the mechanisms that result in differential control of cell surface determinants in the pathogen Salmonella enterica and in the normal member of the human flora Escherichia coli.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042236-15
Application #
8207876
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1998-02-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
15
Fiscal Year
2012
Total Cost
$325,557
Indirect Cost
$129,537
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Groisman, Eduardo A; Hollands, Kerry; Kriner, Michelle A et al. (2013) Bacterial Mg2+ homeostasis, transport, and virulence. Annu Rev Genet 47:625-46
Townsend 2nd, Guy E; Raghavan, Varsha; Zwir, Igor et al. (2013) Intramolecular arrangement of sensor and regulator overcomes relaxed specificity in hybrid two-component systems. Proc Natl Acad Sci U S A 110:E161-9
Choi, Jeongjoon; Groisman, Eduardo A (2013) The lipopolysaccharide modification regulator PmrA limits Salmonella virulence by repressing the type three-secretion system Spi/Ssa. Proc Natl Acad Sci U S A 110:9499-504
May, John F; Groisman, Eduardo A (2013) Conflicting roles for a cell surface modification in Salmonella. Mol Microbiol 88:970-83
Yeo, Won-Sik; Zwir, Igor; Huang, Henry V et al. (2012) Intrinsic negative feedback governs activation surge in two-component regulatory systems. Mol Cell 45:409-21
Kato, Akinori; Chen, H Deborah; Latifi, Tammy et al. (2012) Reciprocal control between a bacterium's regulatory system and the modification status of its lipopolysaccharide. Mol Cell 47:897-908
Chen, H Deborah; Jewett, Mollie W; Groisman, Eduardo A (2012) An allele of an ancestral transcription factor dependent on a horizontally acquired gene product. PLoS Genet 8:e1003060
Jarvik, Tyler; Smillie, Chris; Groisman, Eduardo A et al. (2010) Short-term signatures of evolutionary change in the Salmonella enterica serovar typhimurium 14028 genome. J Bacteriol 192:560-7
Mitrophanov, Alexander Y; Groisman, Eduardo A (2010) Response acceleration in post-translationally regulated genetic circuits. J Mol Biol 396:1398-409
Raghavan, Varsha; Groisman, Eduardo A (2010) Orphan and hybrid two-component system proteins in health and disease. Curr Opin Microbiol 13:226-31

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