Urinary Tract Infection as a Model for Innate Mucosal Immunity

M. Samuelsson; G. Bergsten; H. Fischer; I. Leijonhufvud; A. C. Lundstedt; P. Samuelsson; M. L. Svensson; B. Wullt; C. Svanborg; D. Karpman; B. Wullt

doi:10.1128/9781555817671.ch8

Chapter 8 : Urinary Tract Infection as a Model for Innate Mucosal Immunity

Authors: M. Samuelsson¹, G. Bergsten¹, H. Fischer¹, I. Leijonhufvud¹, A. C. Lundstedt¹, P. Samuelsson¹, M. L. Svensson¹, B. Wullt¹, C. Svanborg¹, D. Karpman², B. Wullt³

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Affiliations: 1: Department of Laboratory Medicine, Division of Microbiology, Immunology, and Glycobiology, Lund University, Lund, Sweden; 2: Department of Pediatrics, Lund University Hospital, Lund, Sweden; 3: Department of Urology, Lund University Hospital, Lund, Sweden

Content Type: Monograph

Publication Year: 2004

Category: Immunology; Clinical Microbiology

Book DOI: 10.1128/9781555817671

Chapter DOI: 10.1128/9781555817671.ch8

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Abstract:

Most studies on innate immunity have focused on macrophages, as these cells are crucial defenders against infection of the systemic compartments. This chapter talks about (i) the molecular mechanisms used by bacteria to trigger the innate host response, (ii) neutrophils as effectors of the antimicrobial defense of the urinary tract, and (iii) genetic defects in innate host defense pathways that explain the susceptibility to urinary tract infections (UTIs). P-fimbriated Escherichia coli is used to examine the role of recognition receptors and toll-like receptor-4 (TLR4) coreceptors in epithelial cell activation. Cell activation can proceed in two steps, involving a primary ligand-binding receptor and a second receptor responsible for transmembrane signaling, which in this model is TLR4. The authors have speculated that epithelial unresponsiveness to lipopolysaccharide (LPS) may be essential to maintain mucosal integrity, and have used the murine IL-8 receptor homologue (mIL-8Rh-/-) mouse to study chemokines and chemokine receptors in the defense against UTI. Inactivation of a single gene encoding mIL-8Rh is sufficient to convert the mice from a resistant to a susceptible phenotype, as defined both by acute disease susceptibility and by chronic disease development. The chemokine receptors must be functional to avoid the trapping of neutrophils that results in tissue destruction.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8

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Infection and Immunity: 0.51934534
Urinary Tract Infections: 0.51202637

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Urinary Tract Infection as a Model for Innate Mucosal Immunity

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FIGURE 1

Innate responses at mucosal surfaces. (A) The epithelial barrier is breached by pathogenic bacteria. Following the initial adherence, the bacteria activate the epithelial cells to release of mediators of inflammation, immunity, and cell differentiation. (B) In our model, attachment is mediated through P fimbriae. Cell surface GSLs serve as recognition receptors and signaling is via TLR4. (C) The two-step model of the innate host response in the human urinary tract. Step 1: the adhering bacteria break the inertia of the mucosal barrier by triggering a cellular cytokine response. Step 2: the IL-8 chemokine family and the CXCR1 receptor support neutrophil migration across the epithelium and into the urine and, in the process, infection is cleared.

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FIGURE 1

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FIGURE 2

Bacterial clearance is independent of specific immunity. (A) Kinetics of bacterial clearance. The initial reduction in bacterial numbers and activation of the mucosal response are followed by the neutrophil-dependent phase of bacterial clearance. There is no preexisting specific immune response, and infection is cleared before such a response can be activated. (B) Bacterial clearance is efficient in immunodeficient mice, but deficient in TLR4 mutant mice ( Hagberg et al., 1983 ).These experiments have been repeated in TCR KO and RAG KO mice ( Frendeus et al., 2001a ).The results show that bacterial clearance from the urinary tract depends on the innate immune system. n.s., not significant.

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FIGURE 2

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FIGURE 3

Specific adherence as a mechanism of tissue targeting. (A) P-fimbriated E. coli adhering to a human urinary tract epithelial cell (bright-field microscopy; enlargement, ×1,000). (B) Fimbriae are adhesive organelles. Fimbrial expression (platinum-shadowed electron microscopy; enlargement, ×15,000). (C) Mechanism of adherence.The PapG adhesin at the fimbrial tip recognizes receptor epitopes defined by the Galα1-4Galβ disaccharide in cell surface GSLs. This interaction initiates the mucosal response. (D) Disease association of P-fimbrial expression. P fimbriae are expressed by >95% of strains causing acute pyelonephritis but <20% of asymptomatic carrier strains and commensal fecal strains.

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FIGURE 4

Consequences of TLR4 and CXCR1 deficiencies. Step 1: the bacteria bind to the primary targeting receptors and trigger inflammation.The specificity is determined by the PapG protein on the fimbrial tip and the Galα1-4Galβ receptor motif. Activation is through TLR4. Inactivation of the TLR4 signal aborts the inflammatory cascade. This results in asymptomatic bacterial carriage of the bacteria. Step 2: if TLR4 is functional and the response is activated, the epithelium will secrete inflammatory mediators. Neutrophils will be recruited to the site to deal with the infection. In the presence of the human IL-8 receptor, CXCR1, the neutrophils can squeeze through the tight junctions and enter the lumen with their cargo of phagocytosed bacteria.This will eventually result in a clearance of the infection and pyuria, one of the classic signs of an ongoing UTI. In the absence of CXCR1, the neutrophils are trapped under the epithelial barrier.This will inevitably result in tissue damage as the neutrophils release their contents in the tissues.

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FIGURE 4

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