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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Alexander, William A
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Yale University
Schools of Medicine
New Haven
United States
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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
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
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
Fass, Ephraim; Groisman, Eduardo A (2009) Control of Salmonella pathogenicity island-2 gene expression. Curr Opin Microbiol 12:199-204
Mitrophanov, Alexander Y; Groisman, Eduardo A (2008) Positive feedback in cellular control systems. Bioessays 30:542-55
Perez, J Christian; Latifi, Tammy; Groisman, Eduardo A (2008) Overcoming H-NS-mediated transcriptional silencing of horizontally acquired genes by the PhoP and SlyA proteins in Salmonella enterica. J Biol Chem 283:10773-83
Lee, Hyunwoo; Hsu, Fong-Fu; Turk, John et al. (2004) The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. J Bacteriol 186:4124-33

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