biological mechanisms Streptococcus pneumoniae virulence factors Mycobacterium tuberculosis pathogenesis Bacillus anthracis vaccine development

Transcription

1 Bacteriology at UAB Streptococcus pneumoniae Mycobacterium tuberculosis Bacillus anthracis Mycoplasma biological mechanisms virulence factors pathogenesis vaccine development drug development

2 Bacteriology at UAB Streptococcus pneumoniae Briles, David Hollingshead, Susan Nahm, Moon Pritchard, David Wu, Hui Yother, Janet Streptococcus pneumoniae; vaccines Microbial variation, streptococci Vaccines; Streptococcus pneumoniae Glycobiology; streptococci Streptococci, glycoproteins, biofilms Capsules, streptococci

3 Molecular mechanisms of virulence proteins of Streptococcus pneumoniae and their use as vaccine antigens. David E. Briles, PhD Departments of Microbiology and Pediatrics University of Alabama at Birmingham

4 coiled coil α-helix proline-rich choline-binding PspA PspC / CbpA Neuraminidase A Hyaluronidase Pneumococcal Virulence factors PcpA Lipoteichoic Acid Protection-eliciting proteins are indicated by colors IgA1 Protease Phosphocholine Cell Membrane Pneumolysin Autolysin Cell Wall Capsular Polysaccharide Teichoic Acid

5 Financial support: NIH, Gates Foundation, PATH Aims: to develop a pneumococcal vaccine based on a mixture of pneumococcal protein antigens to develop a rapid test for pneumococcal infection

6 Janet Yother, Ph.D. Streptococcus pneumoniae capsular polysaccharide synthesis and regulation dexb A B CD ET F G H I J KPL M N O alia Cps2H (Wzy) Released Cps2J (Wzx) Peptidoglycan A C D~P undecaprenyl phosphate Membrane B Cps2T Cps2F Cps2G Cps2I Und-P Cps2E TDP Rha UDP Glc UDP GlcUA Cps2NMO Cps2K TDP UDP Cytoplasm Cps2L Glc-1-P GalU PGM Glc-6-P

7 Janet Yother, Ph.D. Streptococcus pneumoniae capsular polysaccharide synthesis and regulation Synthase-dependent capsule synthesis ENZYME? High UDP-GlcUA TRANSITION INITIATION High UDP-Glc OLIGOSACCHARIDE DISSOCIATION SYNTHESIS Low UDP-GlcUA HIGHLY PROCESSIVE SYNTHESIS EJECTION Frequency / Chain Length Determined by [UDP-GlcUA]

8 Moon Nahm Vaccine; S. pneumoniae; bacterial pathogenesis; immunity Bratcher and Nahm. J Clin Microbiol Calix and Nahm. J Infect Dis : Bratcher et al., Microbiology : 555 Zartler et al. Carbohydr Res :2586 Seo et al. Clin Vaccine Immunol :1187. Park et al. Infect Immun :3374.

9 Bacteriology at UAB Mycobacterium tuberculosis Niederweis, Michael Outer membrane proteins of M. tuberculosis Steyn, Adrie Virulence of Mycobacterium tuberculosis

10 Transport across the outer membrane of M. tuberculosis Niederweis et al. (2010), Trends Microbiol. 18, Uptake sugars lipids/fatty acids ions (Fe 2+, Cu 2+ ) drugs lipids sugars Cu + drugs Export 100 nm 100 nm

11 The Mycolab at UAB Science: OMPs of Mtb: novel proteins, essential functions, medically important Lab: 5 postdocs, 5 graduate students, 2 technicians Financial support: $700,000 per year National Institutes of Health (NIH) Potts Memorial Foundation Center for AIDS Research of UAB Heiser Foundation, New York Publications Faller et al. (2004). Science 303, 1189 Hoffmann et al. (2008). Proc. Natl. Acad. Sci. USA 105, 3963 Song et al. (2008). Tuberculosis 88, 526 Danilchanka et al. (2008). Antimicrob. Agents Chemother. 52, 2503 Butler et al. (2008). Proc. Natl. Acad. Sci. USA 105, Huff et al. (2009). J. Biol. Chem 284, 10223

12 Adrie Steyn Mechanism of Mycobacterium tuberculosis virulence Singh et al. PLoS Pathog e Kumar et al., J Biol Chem Singh et al. Proc Natl Acad Sci U S A Kumar et al. Proc Natl Acad Sci U S A

13 Bacteriology at UAB Other bacteria: Atkinson, Prescott Dybvig, Kevin Higgins, N. Patrick Turnbough, Charles Mycoplasma; Asthma Mycoplasma; genetics Mobile DNA Bacillus anthracis, gene regulation

14 Kevin Dybvig Mycoplasmas; genetics; phenotypic switching; DNA rearrangements Simmons and Dybvig. FEMS Microbiol Lett : Daubenspeck et al. Mol Microbiol. 2009;72: Luo et al. FEMS Microbiol Lett. 2009;290: Luo et al. Infect Immun. 2008;76: Dybvig et al. Infect Immun. 2008;76: French et al. Mol Microbiol. 2008;69:67-76.

15 Structure and Function of the B. anthracis Exosporium Turnbough Lab Bacillus anthracis core causes anthrax bioterroism agent infectious spores surrounded by an exosporium exosporium required for spore viability and infectivity l l ~20 exosporium proteins and glycoproteins are known. They are assembled into a complex structure via covalent linkages by novel mechanisms. Research focus: mechanisms and functions of exosporium protein covalent modifications (glycosylation, multi-site phosphorylation, isopeptide bond formation). Recent Publications: Mol. Micro. 76: (2010) & J. Bacteriol. 192: (2010).

16 Regulation of Pyrimidine Gene Expression in Bacteria: Repression without Repressors Turnbough Lab l l l With rare exceptions, in bacteria (e.g., E. coli and B. subtilis) the mechanisms that regulate expression of pyrimidine biosynthetic and salvage operons do not involve the participation of DNA-binding repressor or activator proteins. Instead, regulation occurs by mechanisms or combinations of mechanisms that rely entirely on the basic machinery of transcription or coupled transcription and translation. Such mechanisms include transcription attenuation, reiterative transcription, and/or transcription start-site switching. The Turnbough lab is working on the elucidation of these regulatory mechanisms at the molecular level and also on the description of new mechanisms of gene regulation without accessory proteins. l Example: Attenuation control of pyrg transcription via CTP-sensitve reiterative transcription in Bacillus subtilis. The pyrg gene encodes CTP synthetase, which produces CTP from UTP as the last step in pyrimidine nucleotide biosynthesis. Recent Reviews: Microbiol. Mol. Biol. Rev. 72: (2008) & Mol. Micro. 69:10-14 (2008).