Bacillus anthracis is a spore-forming microbe and the causative agent of gastrointestinal (GI) anthrax, a disease that affects all mammals including humans. The mechanisms of B. anthracis spore invasion across intestinal epithelia and the pathogenesis of GI anthrax were heretofore not known. We show here that B. anthracis spores germinate in the intestinal tract of infected mice and guinea pigs. Vegetative bacilli invade the intestinal tract by a mechanism requiring the S-layer protein BslA, whose structural gene is located on the pathogenicity island of the pXO1 virulence plasmid, a distinctive feature of virulent B. anthracis. BslA binds ?1 integrin and this association promotes uptake of bacilli into host cells. We propose a model whereby BslA- mediated uptake of B. anthracis into intestinal cells enables pathogen invasion of the GI tract and dissemination throughout host tissues. BslA function requires a surface (S)-protein layer with 22 S-layer associated proteins (BSLs). We propose that BSLs are responsible for the broad host range of GI anthrax among mammals. BSLs associate via S-layer homology (SLH)-domains with secondary cell wall polysaccharide (SCWP), a peptidoglycan linked carbohydrate polymer with trisaccharide repeat structure. Pyruvylation and acetylation of SCWP and a specialized SecA2-SlaP-SlaQ secretion pathway are prerequisites for S-layer function. This application seeks to understand the molecular basis for GI anthrax by identifying B. anthracis and host genes involved in pathogen invasion and replication. We also seek to reveal S-layer assembly mechanisms and functions that are crucial for the invasive attributes of B. anthracis. Finally, we propose to study the SCWP, whose synthesis is essential for S-layer assembly. Ultimate goal of our research is a detailed appreciation of the pathogenesis of GI anthrax, which enables the unique life-style of B. anthracis.
This proposal explores the basic mechanisms whereby Bacillus anthracis causes gastrointestinal anthrax, a disease that affects all mammals including humans. The result of the proposed work are expected to be broadly informative for the appreciation of bacterial envelope assembly and function and the pathogenesis of gastrointestinal infections by microbial pathogens.
| Chateau, Alice; Lunderberg, Justin Mark; Oh, So Young et al. (2018) Galactosylation of the Secondary Cell Wall Polysaccharide of Bacillus anthracis and Its Contribution to Anthrax Pathogenesis. J Bacteriol 200: |
| Callegan, Michelle C; Parkunan, Salai Madhumathi; Randall, C Blake et al. (2017) The role of pili in Bacillus cereus intraocular infection. Exp Eye Res 159:69-76 |
| Missiakas, Dominique; Schneewind, Olaf (2017) Assembly and Function of the Bacillus anthracis S-Layer. Annu Rev Microbiol 71:79-98 |
| Oh, So-Young; Lunderberg, J Mark; Chateau, Alice et al. (2017) Genes Required for Bacillus anthracis Secondary Cell Wall Polysaccharide Synthesis. J Bacteriol 199: |
| Liszewski Zilla, Megan; Chan, Yvonne G Y; Lunderberg, Justin Mark et al. (2015) LytR-CpsA-Psr enzymes as determinants of Bacillus anthracis secondary cell wall polysaccharide assembly. J Bacteriol 197:343-53 |
| Nguyen-Mau, Sao-Mai; Oh, So-Young; Schneewind, Daphne I et al. (2015) Bacillus anthracis SlaQ Promotes S-Layer Protein Assembly. J Bacteriol 197:3216-27 |
| Lunderberg, J Mark; Liszewski Zilla, Megan; Missiakas, Dominique et al. (2015) Bacillus anthracis tagO Is Required for Vegetative Growth and Secondary Cell Wall Polysaccharide Synthesis. J Bacteriol 197:3511-20 |
| Oh, So-Young; Richter, Stefan G; Missiakas, Dominique M et al. (2015) Glutamate Racemase Mutants of Bacillus anthracis. J Bacteriol 197:1854-61 |
| Liszewski Zilla, Megan; Lunderberg, J Mark; Schneewind, Olaf et al. (2015) Bacillus anthracis lcp Genes Support Vegetative Growth, Envelope Assembly, and Spore Formation. J Bacteriol 197:3731-41 |
| Wang, Ya-Ting; Missiakas, Dominique; Schneewind, Olaf (2014) GneZ, a UDP-GlcNAc 2-epimerase, is required for S-layer assembly and vegetative growth of Bacillus anthracis. J Bacteriol 196:2969-78 |
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