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Chapter 4 : Pathogenesis and Virulence Factor Regulation

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Abstract:

is a gram-positive bacterium that is a component of the commensal flora of the skin and the nares. is responsible for causing significant morbidity and mortality, resulting in nearly 300,000 hospitalizations and 19,000 deaths in the United States annually. Surface-associated factors enable to bind to biotic surfaces, abiotic surfaces, and itself. The ability to adhere to varied surfaces likely represents the first step during the infection process, in which the bacterium attaches and grows on different tissues. The ability of to infect many tissues in the mammalian body suggests that this bacterium is extremely efficient at adapting to different environments. In order to monitor the density of the population and prevent starvation and/or clearance by the host, most bacteria secrete small molecules into the extracellular milieu that accumulate in response to an increase in the number of bacteria in a defined space. These so-called autoinducers are sensed by the entire population, triggering a signaling cascade that informs the community that quorum has been attained. Numerous regulatory networks work with or against one another to carefully coordinate the precise expression and production of a large collection of virulence factors that play different roles in infection. A critical layer of complexity to this topic is the tremendous strain-to-strain variability seen in clinical isolates. This variability often influences the expression of virulence factors, which directly alters the pathogenic trait of clinical isolates.

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 1

Microarray analysis of strains and growth conditions. Blue indicates genes which were downregulated in indicated condition or mutant, red indicates upregulated genes, and yellow indicates no change. White denotes that the gene was not included in the particular microarray analysis. Transcription profiles of strains LAC and MW2 following neutrophil (PMN) phagocytosis were performed by Malachowa et al. ( ). Transcription profiles of strains LAC and MW2 were performed by Voyich et al. ( ). Comparison of the transcription profiles between USA300 CAMRSA wild-type (WT) strain LAC and a Δ or a Δ isogenic mutant strain were performed by Cheung et al. ( ) and Nygaard et al. ( ), respectively. Experiments comparing the transcription profile of the USA400 CA-MRSA WT strain MW2 to that of a Δ or Δ or an Δ isogenic mutant strain were performed by Queck et al. ( ) and Voyich et al. ( ), respectively. doi:10.1128/9781555818524.ch4f1

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 2

regulates the production of virulence factors in a growth phase-dependent manner. Shown is a schematic representation of the association of growth in vitro (black line) and the production of surface virulence factors (green line) and cytotoxins (red line). Early in log phase, produces high levels of surface proteins and low levels of cytotoxins. In contrast, at the transition between late log and stationary phase, concomitantly downregulates the production of surface proteins and upregulates the production of cytotoxins. doi:10.1128/9781555818524.ch4f2

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 3

The Agr system. The diagram depicts the Agr quorum sensing TCS. Upon reaching quorum, the Agr TCS is activated by binding of AIP to AgrC, resulting in the autophosphorylation of AgrC. AgrC then phosphorylates ArgA, which subsequently binds and activates the P2 and P3 promoters. Activation of the P2 promoter results in the expression of the multicistronic RNAII transcript and increased production of AgrB, AgrD, AgrC, and AgrA, and thus continuous activation of the system. Activation of the P3 promoter results in the expression of RNAIII transcript, which is itself a regulatory RNA and also codes for delta-hemolysin. Production of RNAIII regulates the expression and production of virulence factors directly via RNAIII-target mRNA interactions and indirectly via RNAIII-mediated inhibition of Rot synthesis. Rot (see p. 66) represses the expression of cytotoxin-encoding genes and activates the expression of genes coding for cell surface proteins. doi:10.1128/9781555818524.ch4f3

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 4

The Agr system AIPs. Shown is a schematic representation of the four different AIP molecules (AIP I to IV). The sequences of AIP I and AIP IV differ only by a single amino acid in the thiolactone ring. doi:10.1128/9781555818524.ch4f4

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 5

Structure and mechanism of action of RNAIII. The diagrams depict the secondary structure of RNAIII (A) and the 5′ UTR sequences of (B) and (C). Binding of RNAIII to the 5′ UTR sequence results in the formation of a double-stranded RNA molecule that is recognized and degraded by RNase III. In contrast, binding of RNAIII to the 5′ UTR sequence enables translation of the mRNA. doi:10.1128/9781555818524.ch4f5

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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Figure 6

The SaeRS TCS. The diagram depicts the organization of the locus and the predicted localization of the Sae components. The P3 promoter of the is constitutively active, resulting in basal level expression of and . Upon exposure to a signal (lightning bolt), SaeS is autophosphorylated, followed by phosphotransfer from SaeS to SaeR. Phosphorylation of SaeR enhances the DNA binding activity of this transcriptional regulator, resulting in binding and activation of the P1 promoter and thus autoinduction. In addition, activated SaeR binds to target promoters containing the SaeR binding sequence, resulting in their increased expression of these genes. doi:10.1128/9781555818524.ch4f6

Citation: Torres V, Benson M, Voyich J. 2013. Pathogenesis and Virulence Factor Regulation, p 58-78. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch4
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