Helicobacter pylori is a helical rod shaped bacterium that colonizes the human stomach causing clinical outcomes that range from mild gastritis to peptic ulcer and gastric cancers. Most descriptions of H. pylori virulence include the widely-accepted hypothesis that its helical cell shape enhances colonization of the stomach. We recently provided the first experimental support for this theory with the characterization of four cell shape determining genes (csd1, csd2, csd3, ccmA) that promote helical cell curvature and twist through changes in cell wall peptidoglycan (PG) crosslinking and are required for efficient stomach colonization. Alteration of peptide crosslinking within the PG sacculus defines a new mechanism for bacterial cell shape generation;previous studies delineated localized deposition and restriction of new PG deposition as drivers of straight rod and curved rod shapes. Though the mutants described above have lost helical twist, they retain some curvature. Thus much remains to be learned about the precise molecular mechanisms for generating helical shape in H. pylori. This grant builds on our published work with a goal of elucidating the H. pylori helical shape generating program and the contributions of this cell shape program to H. pylori pathogenesis.
Aim 1 will identify and characterize additional genes involved in helical cell shape determination.
Aim 2 will investigate how these genes work together to promote shape using biochemical studies of cell shape proteins and PG cell wall composition.
Aim 3 will investigate possible mechanisms by which the helical cell shape generating program promotes stomach colonization including modulation of swimming behavior and niche utilization within the stomach. Bacteria manifest an impressive diversity of cell shapes that are highly conserved within species but the selective forces leading to conservation of specific shapes are poorly understood. We have established H. pylori as an excellent model to elucidate molecular determinants of helical cell shape and the selective role of shape during host colonization in the Proteobacteria;Csd proteins and CcmA homologues are well conserved among curved to helical Proteobacteria including several other pathogens such as Campylobacter jejuni and Vibrio cholerae. The elucidation of a helical shape generating program required for stomach colonization promises to illuminate new targets for antimicrobial design which are badly needed in H. pylori as current strains display increasing resistance to existing therapies and fits the mission of NIAID to understand and treat infectious diseases.

Public Health Relevance

Evident in its name, Helicobacter pylori is a helical rod shaped bacterium that colonizes the human stomach causing clinical outcomes that range from mild gastritis to peptic ulcer and gastric cancer. We discovered genes that promote helical cell shape by altering the extent of peptide crosslinking in the cell wall. Study of how these cell wall modifications promote helical cell shape and the ability of the bacterium to live in its niche will help us better understand how this bacteria causes disease and uncover new ways to inhibit infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI094839-01A1
Application #
8256474
Study Section
Special Emphasis Panel (ZRG1-IDM-R (02))
Program Officer
Mills, Melody
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$423,554
Indirect Cost
$173,554
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Sycuro, Laura K; Rule, Chelsea S; Petersen, Timothy W et al. (2013) Flow cytometry-based enrichment for cell shape mutants identifies multiple genes that influence Helicobacter pylori morphology. Mol Microbiol 90:869-83
Salama, Nina R; Hartung, Mara L; Muller, Anne (2013) Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol 11:385-99
Sycuro, Laura K; Wyckoff, Timna J; Biboy, Jacob et al. (2012) Multiple peptidoglycan modification networks modulate Helicobacter pylori's cell shape, motility, and colonization potential. PLoS Pathog 8:e1002603