Download The Acute Phase Response

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
Virulence Factors
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Invasion
Penetration
Protection
Nutrition
Dissemination
Overview
• Gene Regulation
• Genetic Organization
• In Vitro Methods for Studying Virulence
Factors
• Protein Secretion
Environmental Pressures Influencing
Virulence Factor Production
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Osmolarity
O2 Concentration
CO2 Concentration
pH
O2 and N intermediates
Lack of nutrients
Inorganic ion concentrations
Environmental Modulation
vs
Phase Variation
Antigenic Variation
CHANGE IN DNA SEQUENCE
Gene Amplification
Gene Rearrangement
CHANGE IN NUMBER OF TRANSCRIPTS
Activators
Repressors
CHANGE IN AMOUNT OF ACTIVE GENE PRODUCT
Covalent
Modification
Proteolytic
Cleavage
Binding to
Host Cell
Proteins
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
Phase Variation I: Gene Inversion
hin
Ph2
H2
H2 protein
Ph2
hin
H2
rH1
Ph1
H1
Ph1
H1
RH1 repressor
RH1
H1 protein
Stages in
interaction of N.
gonorrhoeae with
cultured
mammalian cells
pilE Antigenic Variation
Phase Variation II: Slipped
Strand Mispairing
Transcriptional Regulation
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Fur repressor (ferric uptake repression)
AraC transcriptional activator family
LysR transcriptional activator family
Two-Component Regulatory Systems
Ara C Family
LysR Transcriptional Activator
Family
Membrane Signal Transduction
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
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