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Chapter 21 : Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response

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Abstract:

Defining UTI susceptibility and appropriate therapeutic interventions is essential, in view of the prevalence of these infections and their significance to health and society (for relevant recent reviews see ( ). The clinical appearance of infection reflects the host-response profile, the receptors engaged by specific virulence factors, and the activation of downstream-signaling pathways. Depending on the type of receptor engaged, different signaling pathways are activated, and cascades of innate immune-response effectors activate innate and specific immunity. Specific attachment alerts the host to the presence of virulent bacteria on the epithelial cell surface ( ) and perturbations of host-cell receptors by bacterial P fimbriae initiate the innate immune response ( ) ( Fig. 1A ) through specific transcription factors such as interferon regulatory factors (IRFs) and activator protein 1 (AP-1), which activate numerous, intricate antibacterial-effector functions ( Fig. 2 ). Additional virulence factors disrupt the mucosal barrier and facilitate invasive disease ( ). Their interactions with host cells add to the complexity of the innate immune response through the activation of signaling pathways defined by their cellular receptors ( Fig. 1B , see below). These include fimbriae (type 1, Dr, curli and Afa), flagella, toxins that permeabilize and kill host cells, like hemolysin and cytotoxic-necrotizing factor, and capsule formation, which confers resistance to bactericidal host molecules (such as defensins or antibodies). Interestingly, certain uropathogens actively inhibit innate immune signaling, for example, the Toll/interleukin-1 receptor (TIR) homologous protein TcpC secreted by the bacteria impairs Toll-like receptor (TLR) and myeloid differentiation primary response gene 88 (MYD88)-dependent innate immune responses and promote bacterial survival in the urinary tract ( ). Differences in individual susceptibility are usually deduced from the frequency of infection, from the acute-disease severity and from the sequels. For the purpose of this review, we would like to emphasize that susceptibility parameters such as symptoms and tissue damage are a direct reflection of the host response to the infecting strain, usually its lack of efficiency. Acute pyelonephritis (APN) is a severe and potentially life-threatening infection of the kidneys with systemic involvement and mortality, especially in patients who develop urosepsis. A rapid innate immune response and resulting inflammation in the infected kidney causes symptoms such as flank pain, and the spread of inflammatory mediators, such as interleukin (IL)-6, triggers the systemic host response (fever >38.5°C and general malaise) ( ). The extent of renal tissue involvement varies between APN patients, with a subset developing recurrent infections and tissue damage. Acute infection foci may be detected by dimercaptosuccinic acid (DMSA) scans and more permanent damage by repeated scans or other imaging technology. Recurrent APN in childhood may cause end-stage renal disease, especially in societies with limited access to health care and antibiotic therapy. During the last decades, molecular determinants of APN susceptibility have been identified. These include exaggerated bacterial-virulence profiles and host genetic variants that reduce the efficiency of the effector phase of the antibacterial response, resulting in exaggerated and dysregulated inflammation in APN-susceptible patients ( ).

Citation: Ambite I, Nagy K, Godaly G, Puthia M, Wullt B, Svanborg C. 2017. Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response, p 525-554. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0019-2014
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Figure 1

Initiation of the innate immune response by UPEC. P fimbriae-mediated adherence and TLR4 activation. Bacterial adherence to epithelial surface receptors activates TLR4 and initiates innate immune signaling. Pathogen-specific recognition by the PapG adhesin of Galα1-4-Galβ-receptor motifs in the globoseries of glycosphingolipids. Release of ceramide activates TLR4 signaling, mainly through the TRIF/TRAM adaptors. The MYD88/TIRAP/NF-κB-dependent arm of TLR4 signaling, in contrast, is activated by type 1-fimbriated strains and, to some extent, also by ABU strains (not shown ( )). Genetic variants that affect the expression of receptors also influence the susceptibility to APN. Patients who express high levels of receptors are more susceptible to APN (blood group A P), illustrating the relevance of this mechanism ( ). In ABU patients, TLR4 expression is low and -promoter polymorphisms that reduce TLR4 expression are predominately found in this patient group. Clinical genetic screens have not detected ABU-associated polymorphisms in or . In the murine UTI model, deletions abrogate the innate immune response, as do adaptor-gene deletions, to some extent. As a result, these mice develop ABU rather than symptomatic disease. Abbreviations: galactose (Gal), glucose (Glc), N-acetyl glucosamine (GlcNAc), Toll-like receptor (TLR), Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF), TRIF-related adaptor molecule (TRAM), phosphate group (P), acute pyelonephritis (APN), asymptomatic bacteriuria (ABU), single-nucleotide polymorphism (SNP), myeloid-differentiation primary-response protein 88 (MYD88), polymorphonuclear cells (PMN). Adapted from Ragnarsdóttir et al. ( ), with permission.

Citation: Ambite I, Nagy K, Godaly G, Puthia M, Wullt B, Svanborg C. 2017. Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response, p 525-554. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0019-2014
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Image of Figure 1
Figure 1

Uroepithelial receptors for bacterial ligands. Uroepithelial cells express a number of specific receptors for microbial ligands including TLRs and receptors for adhesins, toxins, and flagella, among others. Importantly, uroepithelial cells do not express CD14 and the initial recognition of Gram-negative bacteria does not involve LPS, unless soluble CD14 is present. TLR5 interacts with bacterial flagellin; TLR11 recognizes uropathogens through yet undetermined bacterial ligands and TLR2 is activated by bacterial cell wall components. Type 1 fimbriae activate TLR4 signaling through the FimH adhesin, which binds to a variety of mannosylated glycoproteins. Binding to uroplakin particles (UP1a, 1b, 2, and 3a) promotes bacterial internalization. FimH also binds to β1 and α3 integrins, which modulate F-actin dynamics in the mammalian cell. TNFα responses to type 1-fimbriated bacteria are triggered by the glycosyl-phosphatidyl-inositol-anchored CD48 receptor on mast cells and macrophages. The receptor epitopes of UPs, CD48, and integrins, are N-linked high-mannose oligosaccharides. Abbreviations: lipopolysaccharide (LPS), soluble CD14 (sCD14), glycosphingolipids (GSLs), Toll-like receptor (TLR), mannosylated cell-surface glycoprotein (MGP), uroplakin (UP), not applicable (NA), acute pyelonephritis (APN), single-nucleotide polymorphism (SNP), asymptomatic bacteriuria (ABU), recurrent urinary tract infection (rUTI). Adapted from Ragnarsdóttir et al. ( ), with permission.

Citation: Ambite I, Nagy K, Godaly G, Puthia M, Wullt B, Svanborg C. 2017. Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response, p 525-554. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0019-2014
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Figure 2

Transcriptional control of the innate immune response to UPEC. Signaling downstream of TLR4 activates the transcription of innate immune-effector molecules, such as chemokines, cytokines, and antibacterial peptides ( ). Transcription factors are activated by phosphorylation and nuclear translocation, including IRF3 and IRF7, as well as AP-1, a heterodimer of FOS and JUN. In addition, NF-κB is critically involved, (not shown). In clinical studies, promoter polymorphisms that reduce the expression of IRF3 have been associated with susceptibility to acute pyelonephritis. In the murine UTI model, mice lacking develop severe acute infection with mortality, followed by renal damage in surviving mice. Downstream mediators have also been shown to play an essential role for UTI susceptibility, including type 1 IFNs. Relevance of IFNβ has been demonstrated in the murine UTI model, where mutant mice develop severe acute infection with tissue damage. Clinical studies associating IFNβ with UTI susceptibility have not been reported. Abbreviations: phosphate group (P), cyclic AMP-response element-binding (CREB), interferon-regulatory factor (IRF), activator-protein 1 (AP-1), interferon (IFN), interleukin (IL), single-nucleotide polymorphism (SNP), acute pyelonephritis (APN), CC-chemokine ligand 5 (CCL5), not applicable (NA). Adapted from Ragnarsdóttir et al. ( ), with permission.

Citation: Ambite I, Nagy K, Godaly G, Puthia M, Wullt B, Svanborg C. 2017. Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response, p 525-554. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0019-2014
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Figure 3

Neutrophil-dependent clearance of infection. Chronic infection and renal scarring in -deficient patients and -deficient mice. In UTI, neutrophils migrate to the mucosal epithelial barrier, which they cross into the lumen. As a result, infection causes pyuria, which often is used diagnostically, as the neutrophils first phagocytose and kill bacteria and then leave the tissue via this mechanism; tissue damage is prevented. Migration is directed by chemokines, first released by infected epithelial cells and subsequently amplified by neutrophils and other cells, such as mast cells, at the site of infection. In patients prone to APN, CXCR1 expression is reduced compared to age-matched controls and intronic and 3′UTR polymorphisms are more abundant than in controls without UTI. polymorphisms have also been associated with APN susceptibility. In mice lacking the chemokine receptor, neutrophil exit is prevented, however, and a backlog of neutrophils builds up in the tissues. The massive neutrophil infiltrate does not remove the bacteria, as neutrophils from mice lacking 2 have an activation deficiency. Persisting bacteria continue to stimulate chemokine production and neutrophils continue to be recruited, resulting in chronic infection and renal scarring ( ). Abbreviations: CXC-chemokine receptor (CXCR), interleukin (IL), single-nucleotide polymorphism (SNP), not applicable (NA), acute pyelonephritis (APN), untranslated region (UTR).

Citation: Ambite I, Nagy K, Godaly G, Puthia M, Wullt B, Svanborg C. 2017. Susceptibility to Urinary Tract Infection: Benefits and Hazards of the Antibacterial Host Response, p 525-554. In Mulvey M, Klumpp D, Stapleton A (ed), Urinary Tract Infections: Molecular Pathogenesis and Clinical Management, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.UTI-0019-2014
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