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

(A) 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 ( 36 )). 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 A1 P1), illustrating the relevance of this mechanism ( 145 ). In ABU patients, TLR4 expression is low and TLR4-promoter polymorphisms that reduce TLR4 expression are predominately found in this patient group. Clinical genetic screens have not detected ABU-associated polymorphisms in MYD88 or TRIF. In the murine UTI model, Tlr4 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. ( 3 ), with permission.

(B) 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. ( 3 ), with permission.

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 ( 3 , 87 ). 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 Irf3 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. ( 3 ), with permission.

Neutrophil-dependent clearance of infection. Chronic infection and renal scarring in CXCR1-deficient patients and mCxcr2-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. CXCL8 polymorphisms have also been associated with APN susceptibility. In mCxcr2 −/− 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 mCxcr2 have an activation deficiency. Persisting bacteria continue to stimulate chemokine production and neutrophils continue to be recruited, resulting in chronic infection and renal scarring ( 35 ). Abbreviations: CXC-chemokine receptor (CXCR), interleukin (IL), single-nucleotide polymorphism (SNP), not applicable (NA), acute pyelonephritis (APN), untranslated region (UTR).