Chapter 25 : Fimbriae, Signaling, and Host Response to Urinary Tract Infection

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This chapter describes the signaling pathways in the urinary tract and their relevance to asymptomatic carriage, acute symptomatic disease, and chronic infection with tissue damage. There is evidence that P fimbriae enhance bacterial virulence by promoting both intestinal colonization and spread to the urinary tract, by promoting the establishment of bacteriuria, by facilitating the establishment of bacteremia, by activating the innate host response, and by resisting neutrophil killing. P fimbriae use glycosphingolipid receptors (GSLs) as primary receptors to adhere to the host cells and use TLR4 as coreceptors in transmembrane signaling and cell activation. The nonfimbriated strain did not induce a host response in either Tlr4 or Tlr4 mice, demonstrating that P fimbriae and Tlr4 both were needed to trigger the innate host response. The fimbriae have been identified as virulence factors in the murine experimental model of urinary tract infection (UTI) and as colonization factors of the large intestine, but a role in virulence is potentially difficult to reconcile with the occurrence of type 1 fimbriae in both virulent and commensal strains. The GSL recognition receptors are essential for P fimbriae to adhere and to recruit TLR4 for signaling. The expression of receptors for P fimbriae reflects the P blood group, since the receptor structures also act as the P blood group of the host.

Citation: Roche N, Bergsten G, Fischer H, Godaly G, Irjala H, Lundstedt A, Samuelsson P, Svensson M, Ragnarsdottir B, Svanborg C. 2005. Fimbriae, Signaling, and Host Response to Urinary Tract Infection, p 379-394. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch25
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Figure 1

The two steps of the host response to uropathogenic Step 1 involves triggering of the epithelial cells, and step 2 involves the neutrophil-dependent clearance of infection.

Citation: Roche N, Bergsten G, Fischer H, Godaly G, Irjala H, Lundstedt A, Samuelsson P, Svensson M, Ragnarsdottir B, Svanborg C. 2005. Fimbriae, Signaling, and Host Response to Urinary Tract Infection, p 379-394. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch25
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Figure 2

Step 1: host response induction. The PapG adhesin of the P fimbriae adheres to GLS receptors bearing the Gal(α1-4)Galβ epitope. Ceramide is released, and TLR4 is recruited. Ultimately, the cells produce cytokines such as IL-6 and IL-8.

Citation: Roche N, Bergsten G, Fischer H, Godaly G, Irjala H, Lundstedt A, Samuelsson P, Svensson M, Ragnarsdottir B, Svanborg C. 2005. Fimbriae, Signaling, and Host Response to Urinary Tract Infection, p 379-394. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch25
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Figure 3

Step 2: effector phase of the innate host defense. Infected epithelial cells express IL-8 receptors on their surface and produce IL-8. Both IL-8 and the IL-8 receptors guide neutrophils across the epithelial barrier into the urine. In the process, infection is cleared.

Citation: Roche N, Bergsten G, Fischer H, Godaly G, Irjala H, Lundstedt A, Samuelsson P, Svensson M, Ragnarsdottir B, Svanborg C. 2005. Fimbriae, Signaling, and Host Response to Urinary Tract Infection, p 379-394. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch25
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Figure 4

TLR signaling. The adaptor protein MyD88 is used by most TLRs, the probable exception being TLR3. Signaling through TLR4 can occur via MyD88-dependent or MyD88-independent pathways, and TIRAP is needed for MyD88-dependent signaling by TLR2 and TLR4. TLR4 signaling also involves the TRIF/TRAM-dependent but MyD88-independent pathway, which can activate the transcription factors NF-κB interferon regulating factor 3 (IRF-3). Activation of NF-κB or IRF-3 results in the production of IL-6 and IL-8. The TLRs are depicted as dimers, although dimer formation following stimulation has not been confirmed for all TLRs.

Citation: Roche N, Bergsten G, Fischer H, Godaly G, Irjala H, Lundstedt A, Samuelsson P, Svensson M, Ragnarsdottir B, Svanborg C. 2005. Fimbriae, Signaling, and Host Response to Urinary Tract Infection, p 379-394. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch25
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