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

• 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

• 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 RecombinationSlip Strand Mispairing

Opa – N. gonorrhoeae – CTCTT LPS – H. influenzae – CAAT Pilin – H. Influenzae – TA

• Site-specific RecombinationGene Inversion

Flagellin - S. typhimurium

Phase Variation I: Gene Inversion

H2 protein RH1 repressor

hin Ph2 H2 rH1 Ph1 H1

Ph2 hin H2 RH1 Ph1 H1

H1 protein

Stages in interaction of N. gonorrhoeae with cultured mammalian cells

pilE Antigenic Variation

Phase Variation II: Slipped Strand Mispairing

Transcriptional Regulation

• 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