The dormant spores of Bacillus anthracis, the causative agent of anthrax, infect human or animal hosts and tether microbial development to disease pathogenesis. Following pathogen crossing of host epithelia and engulfment by macrophages, spore germination and outgrowth of vegetative cells occurs within phagosomes. Bacilli subsequently escape phagosomal membranes and replicate in the cytoplasm of macrophages. Infected macrophages are eventually lysed, and bacilli then multiply extracellularly in all tissues, including blood, liver, spleen, lungs, brain and intestines. The y-D-polyglutamic acid capsule of B. anthracis provides for resistance to phagocytic killing. Secretion of edema toxin as well as lethal toxin induces apoptosis of immune cells and endothelial tissues. These events mediate host killing, which is followed by spore formation, environmental dissemination and transmission to new hosts. This proposal investigates the role of sortases and anchored surface proteins during the four stages of anthrax pathogenesis - (i) spore entry, (ii) invasion of vegetative bacilli into macrophages or host tissues, (iii) extracellular replication of bacilli, and (iv) spore formation in deceased hosts. Two sortase genes are expressed in vegetative bacilli and under iron starvation conditions (srtA and srtB), as occurs in host tissues. A third sortase gene (srtQ is only expressed during spore formation. Each sortase recognizes specific sorting signals and anchors surface protein substrates in the bacterial envelope, thereby contributing unique properties to the infectious life cycle of B. anthracis. Sortase C anchored BasH and Basl are deposited in spore peptidoglycan. A new and exciting mechanism of spore envelope assembly is described here, as srtC is essential for the formation of infectious spores in host tissues. Sortase B anchored BasK is required for heme-iron scavenging, whereas sortase A anchored BasC and internalin-like BasJ are involved in macrophage replication. Using B. anthracis strains Sterne and Ames for genetic and biochemical analysis, the molecular mechanisms of surface protein and sortase function in anthrax pathogenesis will be addressed. B. anthracis is an important bioterror threat agent and this research proposal will provide future therapeutic and preventive interventions by revealing the underlying biological phenomena of anthrax pathogenesis. ? ? ?
| 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 |
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| 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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