Bacteria assemble remarkable surface structures that interface with their surrounding environment. One such structure is the glycolipid known as lipopolysaccharide (LPS) that covers the surface of gram-negative bacteria. LPS is anchored to the bacterial cell by its lipid anchor known as lipid A. Lipid A is synthesized via a highly conserved pathway at the cytoplasmic face of the inner membrane. This is followed by addition of the core oligosaccharide and transport of the molecule across the inner membrane. The O-antigen polysaccharide is ligated to the core-lipid A in the periplasm completing LPS assembly. During the trafficking of LPS to the bacterial surface, latent enzymes modify the LPS structure contributing towards the diversity seen in LPS structure. For the most part, these enzymes target the lipid A anchor and the inner core oligosaccharide domains of the molecule. Since the lipid A is the bioactive component of LPS, these modifications can have a profound impact on disease, by altering LPS recognition by the mammalian innate immune receptor TLR4- MD2. Additionally, alteration of the LPS structure can directly impact the outer membrane permeability barrier, and bacterial resistance to host antimicrobial peptides. The overall objective of this proposal is to unravel the molecular mechanisms by which two pathogenic organisms, Helicobacter pylori and Campylobacter jejuni, modify their LPS structure and the role these modifications play in virulence. Although related, these pathogens have evolved unique modification machinery perhaps adapted for their specific ecological niche.
The specific aims of the current proposal are: (1) characterization of Helicobacter pylori LPS modification machinery;(2) characterization of lipid A modifications in Campylobacter jejuni;and (3) impact of Helicobacter and Camyplobacter LPS remodeling on the host innate immune response. The completion of the Aims below will directly contribute to our understanding of how LPS modification machinery impacts pathogenesis. Finally, from this work will come new avenues of vaccine development and the ability to generate engineered LPS structures that could serve as potential adjuvants and/or LPS antagonists.
Gram-negative bacteria are responsible for a number of human infectious diseases. On the surface of these bacteria is a molecule called lipopolysaccharide or LPS that activates the human immune system. Bacteria modify their LPS structure which directly impacts disease. This proposal will help determine how bacteria associated with human disease modify their LPS structure possibly leading to novel therapies.
|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|
|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|
|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|
|Boll, Joseph M; Crofts, Alexander A; Peters, Katharina et al. (2016) A penicillin-binding protein inhibits selection of colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii. Proc Natl Acad Sci U S A 113:E6228-E6237|
|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|
|Band, Victor I; Crispell, Emily K; Napier, Brooke A et al. (2016) Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae. Nat Microbiol 1:16053|
|Nowicki, Emily M; O'Brien, John P; Brodbelt, Jennifer S et al. (2015) Extracellular zinc induces phosphoethanolamine addition to Pseudomonas aeruginosa lipid A via the ColRS two-component system. Mol Microbiol 97:166-78|
|Boll, Joseph M; Tucker, Ashley T; Klein, Dustin R et al. (2015) Reinforcing Lipid A Acylation on the Cell Surface of Acinetobacter baumannii Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival. MBio 6:e00478-15|
|Hutterer, Corina; Eickhoff, Jan; Milbradt, Jens et al. (2015) A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations. Antimicrob Agents Chemother 59:2062-71|
|Rubin, Erica J; Herrera, Carmen M; Crofts, Alexander A et al. (2015) PmrD is required for modifications to escherichia coli endotoxin that promote antimicrobial resistance. Antimicrob Agents Chemother 59:2051-61|
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