Regulation of Virulence Genes

1
Regulation of Virulence Genes

• Salyers Whitt Bacterial Pathogenesis A
  Molecular Approach
• ASM Press, 1994
• Dorman, C.J Genetics of Bacterial Virulence.
  Blackwell Scientific Publications, 1994

2
Virulence Factors

• Invasion
• Penetration
• Protection
• Nutrition
• Dissemination

3
Overview

• Gene Regulation
• Genetic Organization
• In Vitro Methods for Studying Virulence Factors
• Protein Secretion

4
Environmental Pressures Influencing Virulence
Factor Production

• Osmolarity
• O2 Concentration
• CO2 Concentration
• pH
• O2 and N intermediates
• Lack of nutrients
• Inorganic ion concentrations

5
Environmental Modulation vs Phase
Variation Antigenic Variation
6
CHANGE IN DNA SEQUENCE CHANGE IN DNA SEQUENCE CHANGE IN DNA SEQUENCE CHANGE IN DNA SEQUENCE CHANGE IN DNA SEQUENCE
Gene Amplification Gene Amplification Gene Rearrangement Gene Rearrangement

CHANGE IN NUMBER OF TRANSCRIPTS CHANGE IN NUMBER OF TRANSCRIPTS CHANGE IN NUMBER OF TRANSCRIPTS CHANGE IN NUMBER OF TRANSCRIPTS CHANGE IN NUMBER OF TRANSCRIPTS
Activators Activators Repressors Repressors

CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT
Covalent Modification Proteolytic Cleavage Binding to Host Cell Proteins
7
Genetic Variation in Pathogenic Bacteria

• Homologous Recombination
• Slip Strand Mispairing
• Opa N. gonorrhoeae CTCTT
• LPS H. influenzae CAAT
• Pilin H. Influenzae TA
• Site-specific Recombination
• Gene Inversion
• Flagellin - S. typhimurium

8
Phase Variation I Gene Inversion
9
Stages in interaction of N. gonorrhoeae with
cultured mammalian cells
10
(No Transcript)
11
pilE Antigenic Variation
12
Phase Variation II Slipped Strand Mispairing
13
Transcriptional Regulation

• Fur repressor (ferric uptake repression)
• AraC transcriptional activator family
• LysR transcriptional activator family
• Two-Component Regulatory Systems

14
Ara C Family
15
LysR Transcriptional Activator Family
16
Membrane Signal Transduction
17
Genetic Organization of Virulence Factors Sources

• Plasmid transformation(horizontal gene transfer)
  e.g Shigella flexneri, Salmonella spp, Yersinia
  spp, Clostridium tetani.
• Phage lysogeny e.g C. botulinus toxins,S.
  pyogenes, C. diphtheria toxin, Cholera toxin
• Pathogenicity Islands
• Transposons
• Integrons

18
Pathogenicity Islands

• Carriage of many virulence genes
• Association with pathogenic species
• Different GC content compared to rest of host
  genome
• Association with tRNA genes and/or insertion
  sequence elements, suggesting phage origin.
• Presence of transposable elements
• Instability