Helicobacter pylori, a Gram-negative microaerophilic rod, colonizes the human stomach infecting nearly one-half of the world's population. The organism has been classified as a class I carcinogen and plays a major etiological role in human gastritis, peptic ulcer disease, and gastric carcinoma. Humans are the only significant reservoir for H. pylori, despite the hostile environment of the gastric mucosa. Therefore, a unique balance must be established in order to permit long-term survival of both the bacterium and its human host. The outer surface of H. pylori and other Gram-negative bacteria consists primarily of lipopolysaccharide that is composed of three distinct structural domains: O-antigen, core, and lipid A. Lipid A, also known as endotoxin, is the membrane anchor of lipopolysaccharide and is the portion of the molecule responsible for its endotoxicity. The modification of the lipid A structure is an emerging theme in Gram-negative bacteria that has been reported to contribute to virulence and bacterial pathogenesis. It has been suggested that the LPS structure of H. pylori has evolved to aid the bacterium in evading the host innate immune system, thereby prolonging bacterial infection. Our overall objective is to unravel the molecular mechanisms by which H. pylori modify the structure of their LPS using biochemical and molecular biological approaches. More specifically, we intend to identify novel enzymes and the genes encoding them that are responsible for modification of the lipid A and core domains of H. pylori LPS.
The specific aims of the current proposal are: (i) characterization of modifications to the inner core region of H. pylori LPS; (ii) characterization of modifications to the phosphate groups of H. pylori lipid A; (iii) characterization of acyl-chain rearrangement of H. pylori lipid A. Humans are constantly exposed to a variety of microorganisms having the potential to cause disease. One such organism is a bacterium known as Helicobacter pylori that lives in the human stomach, a niche where no other microorganism is known to thrive. Infection with H. pylori is a predisposing factor for peptic ulcer disease and stomach cancers. The current proposal will help determine how these unique bacteria are able to survive in the human stomach leading to a disease state. ? ? ?
| Crofts, Alexander A; Giovanetti, Simone M; Rubin, Erica J et al. (2018) Enterotoxigenic E. coli virulence gene regulation in human infections. Proc Natl Acad Sci U S A 115:E8968-E8976 |
| Crofts, Alexander A; Poly, Frédéric M; Ewing, Cheryl P et al. (2018) Campylobacter jejuni transcriptional and genetic adaptation during human infection. Nat Microbiol 3:494-502 |
| Tucker, Ashley T; Leonard, Sean P; DuBois, Cory D et al. (2018) Discovery of Next-Generation Antimicrobials through Bacterial Self-Screening of Surface-Displayed Peptide Libraries. Cell 172:618-628.e13 |
| Crittenden, Christopher M; Herrera, Carmen M; Williams, Peggy E et al. (2018) Mapping phosphate modifications of substituted lipid A via a targeted MS3 CID/UVPD strategy. Analyst 143:3091-3099 |
| Powers, Matthew Joseph; Trent, M Stephen (2018) Expanding the paradigm for the outer membrane: Acinetobacter baumannii in the absence of endotoxin. Mol Microbiol 107:47-56 |
| Crittenden, Christopher M; Akin, Lucas D; Morrison, Lindsay J et al. (2017) Characterization of Lipid A Variants by Energy-Resolved Mass Spectrometry: Impact of Acyl Chains. J Am Soc Mass Spectrom 28:1118-1126 |
| Morrison, Lindsay J; Parker, W Ryan; Holden, Dustin D et al. (2016) UVliPiD: A UVPD-Based Hierarchical Approach for De Novo Characterization of Lipid A Structures. Anal Chem 88:1812-20 |
| Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr et al. (2016) Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies. Proc Natl Acad Sci U S A 113:E3609-18 |
| Petrou, Vasileios I; Herrera, Carmen M; Schultz, Kathryn M et al. (2016) Structures of aminoarabinose transferase ArnT suggest a molecular basis for lipid A glycosylation. Science 351:608-12 |
| Henderson, Jeremy C; Zimmerman, Shawn M; Crofts, Alexander A et al. (2016) The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer. Annu Rev Microbiol 70:255-78 |
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