Chapter 7 : Uropathogenic Virulence and Gene Regulation

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This chapter describes the virulence and regulation of chaperone-usher pathway (CUP) pili, focusing on type 1 and P pili in uropathogenic (UPEC), the most common cause of urinary tract infections (UTIs). UPEC and in general heavily rely on CUP pili to mediate attachment to biotic and abiotic surfaces. The pathogenesis of community-acquired UPEC UTI is thought to begin with UPEC colonization of the periurethral area from the fecal flora. Depending on the specific niche UPEC inhabits, it encounters different elements of the immune response as well as different environmental pressures, necessitating precise gene regulation. The ability of UPEC to transcend the acute population bottleneck is described in detail. In addition to up-regulation of genes involved in general metabolism, several genes classified as being involved in removal of reactive oxygen species and hydrophobic compounds were also upregulated. Further, negative cross-regulatory interactions between pili may serve to divert resources to the conditions most effective for persistence or transit throughout hosts. Antivirulence compounds such as pilicides and mannosides represent novel strategies to translate basic knowledge from the investigation of pilus structure and function into new therapeutics that may have efficacy in treating UTIs by affecting CUP expression and function.

Citation: Schwartz D, Hultgren S. 2013. Uropathogenic Virulence and Gene Regulation, p 135-155. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch7
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Figure 1

Model of type 1 pilus biogenesis. (A) Subunits are secreted across the Sec apparatus and immediately bound by the cognate periplasmic chaperone, the absence of which results in subunit misfolding and degradation. The chaperone donates its G1 β-strand to the subunit to complete its incomplete Ig-like fold in donor strand complementation. (B) The chaperone then delivers the subunit to the NTD of the membrane usher, FimD. The subunit is then transferred to the CTD, where DSE occurs with the previously added subunit. P pilus biogenesis occurs in a similar fashion. IM, inner membrane; OM, outer membrane. Panel A was modified with permission from John Wiley and Sons from Henderson et al., 2011, in .doi:10.1128/9781555818524.ch7f1

Citation: Schwartz D, Hultgren S. 2013. Uropathogenic Virulence and Gene Regulation, p 135-155. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch7
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Image of Figure 2
Figure 2

Pathogenesis of UPEC UTI. (A) A population of UPEC from the gut is introduced into the bladder, where the bacteria attach to the epithelial surface with the FimH adhesin at the tip of type 1 pili. (B) UPEC invades the superficial facet cells of the bladder within the first hour of infection. (C) UPEC replicates within the facet cells in a type 1 pilus-dependent manner unlessthe bacteria are expelled via a TLR4-dependent process or infected epithelial cells are jettisoned by an apoptotic mechanism. These processes constitute an intracellular bottleneck whereby unique genetic diversity, depicted here with colored bacteria, is decreased. (D) UPEC organisms form clonal IBCs within the cytoplasm of superficial facet cells of the bladder. (E) Micturition and neutrophils eliminate the majority of luminal bacterial clones constituting an extracellular population bottleneck. Between 16 and 24 hpi, UPEC organisms flux out of the IBC, with some bacteria becoming filamentous to become the dominant population of the bladder. Additional UPEC clones descend from the infected kidneys, adding unique diversity to the bladder population. (F) If a high number of IBCs is formed early (D), chronic cystitis is likely to develop, marked by bacterial replication in the lumen of the bladder and adherence to the tissue via type 1 pili. The genetic diversity of this bacterial population is higher than if the infection resolves with formation of QIRs (G). doi:10.1128/9781555818524.ch7f2

Citation: Schwartz D, Hultgren S. 2013. Uropathogenic Virulence and Gene Regulation, p 135-155. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch7
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Figure 3

Type 1, P, and S pilus regulation. (A) Type 1 pili are transcriptionally regulated by recombinases that invert the promoter, . FimE binds the inverted repeats, turning the promoter OFF. FimB can invert the promoter bidirectionally; however, its major function is turning the promoter ON. The functionally redundant recombinases FimX and IpbA can also turn the promoter ON, whereas IpuA functions similarly to FimB. Lrp and CAP inhibit FimB-mediated OFF-to-ON inversion. (B) The operon is regulated via differential Dam methylation. In the ON orientation, PapI-Lrp complexes bind the distal methylation sites, allowing RNA polymerase to transcribe the genes. Binding of Lrp to proximal GATC sites prevents Dam methylation and RNA polymerase binding, shutting down P pilus transcription. (C) The cross-regulation between pilus operons serves to ensure appropriate adhesin expression for in vivo niche. PapI binds the operon and enhances its transcription. PapB and SfaB inhibit FimB-mediated OFF-to-ON inversion of the promoter, preventing type 1 pilus transcription. CAP, catabolite activator protein. doi:10.1128/9781555818524.ch7f3

Citation: Schwartz D, Hultgren S. 2013. Uropathogenic Virulence and Gene Regulation, p 135-155. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch7
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Table 1

Distribution of CUP pili in sequenced UPEC genomes

Citation: Schwartz D, Hultgren S. 2013. Uropathogenic Virulence and Gene Regulation, p 135-155. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch7

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