Chapter 2 : Chronic versus Acute Infection States

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This chapter reviews the observations supporting the idea that acute and chronic infections represent distinct modes of host-pathogen interaction. The virulence factors associated with acute infections and chronic infections are discussed, with a focus on data obtained from human subject-based studies, when possible. expresses many virulence factors that can damage host cells and which contribute to infection in both humans and animal models. Ectopic expression of virulence factor regulator (Vfr) in strains restored expression of ExoS, type IV pilus (TFP), and elastase, confirming that downregulation of Vfr is responsible for decreased virulence factor expression in mucoid strains under the conditions evaluated in this study. While it is clear that regulators of TFP biogenesis and function are intimately associated with the control of Vfr and cyclic AMP (cAMP) expression, the mechanism that links twitching motility and Vfr remains to be elucidated. rsmZ and rsmY are two sRNAs that interact with the RNA binding protein RsmA. The paper by Bordi and coworkers also provides the first data that rsmY and rsmZ are not functionally redundant. Increased expression of T6SS genes, whose translation is negatively regulated by RsmA, specifically requires increased expression of the rsmZ sRNA. Most bacterial pathogens, included, use their virulence factors for the primary purpose of gaining access to nutrients rather than for causing damage to specific hosts. The chapter focuses on a few examples of regulatory networks that broadly impact virulence factor expression.

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Figure 1

Vfr-cAMP dependent regulation of virulence factor expression. CyaB is the predominate adenylate cyclase that generates cAMP, which activates transcription of virulence genes upon binding to Vfr. Vfr also activates lasR transcription in a cAMP-independent fashion. The TFP biogenesis factors FimV, FimL, and ChpA all positively regulate Vfr-cAMP. FimL affects Vfr levels during growth on agar surfaces when TFP-dependent motility is high. MucA is a negative regulator of AlgU, which itself negatively regulates Vfr via AlgR. CpdA is a phosphodiesterase that breaks down cAMP. doi:10.1128/9781555818524.ch2f1

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Figure 2

Expression of genes associated with chronic infection by the GacS/A two-component system. GacA activation by the GacS results in GacA phosphorylation, dimerization, and (presumably) binding to the and promoters. The and sRNAs bind to and sequester RsmA, thereby allowing translation of mRNAs encoding T6SS genes and enzymes involved in Psl (and Pel) EPS synthesis and secretion. Hypothetical negative regulators of the T3SS are presumably also expressed under these conditions. The grey molecule represents one of the three sensor kinases (PA1611, PA1976, and PA2824) shown to phosphorylate HptB in vitro. Phosphorylated HptB can phosphorylate and thereby activate the serine/threonine phosphatase activity of PA3346, for which PA3347 is a substrate. Dephosphorylation of PA3347 is hypothesized to favor sequestration of an anti-sigma factor, thereby allowing a putative sigma factor to bind to and activate the promoter. RetS is presumably inactive (dimerized?) under these conditions. Proteins whose deletion inhibits chronic gene expression are colored blue; those whose deletion favors chronic gene expression are colored red. Sensor kinase domains are schematized as follows: HK domains, rectangles; receiver domains, diamonds; and histidine phosphotransfer domains, circles. Yellow circles indicate domains with phosphoacceptor histidines or aspartates, while curved blue arrows indicate phosphotransfer reactions documented in vitro. The functions of LadS in this signaling pathway are not established. IM, inner membrane. doi:10.1128/9781555818524.ch2f2

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Figure 3

Expression of genes associated with acute infection by the GacS/A two-component system. Binding of an unknown ligand to the periplasmic domain of RetS is hypothesized to disrupt RetS homodimerization and to increase the likelihood of RetS-GacS interactions, which inhibit GacS autophosphorylation and phosphotransfer to GacA. Under these conditions, sRNA transcript levels are low and free RsmA can bind to target mRNAs, including those encoding T6SS genes and the operon. Blue arrows indicate phosphotransfer reactions that occur in vitro; their occurrence as an in vivo signaling pathway is speculative but based on the phenotypes of bacteria in which these gene products (RetS, HptB, PA3346, and PA3347) are not expressed. IM, inner membrane. doi:10.1128/9781555818524.ch2f3

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Table 1

Activities associated with T3SS effectors of

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Table 2

Examples of mutations accumulated by during chronic pulmonary infection in CF patients

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2
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Table 3

Other regulators implicated in virulence factor expression

Citation: Kazmierczak B, Murray T. 2013. Chronic versus Acute Infection States, p 21-39. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch2

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