Chapter 21 : Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection

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Microbial determinants of acute-disease severity and tissue damage have been extensively studied, but less is known about genetic variation influencing host susceptibility. This chapter discusses two candidate genes with strong effects on the innate immune response and the antibacterial defense in the urinary tract and with major but opposite effects on urinary tract infection (UTI) susceptibility. The chapter explains that defects in TLR4 expression are protective and associated with asymptomatic bacteriuria (ABU) while defects in CXCR1 expression promote acute pyelonephritis (APN) and renal scarring. C3H/HeJ mice, then known as lipopolysaccharide (LPS)-nonresponder mice, had an increased susceptibility to UTI, as shown by delayed bacterial clearance. It also had an impaired innate immune response, suggesting that defects in innate immunity are of great importance for the antibacterial defense of the urinary tract. Studies of the murine model showed that the antibacterial defense of the urinary tract mucosa relies on innate immunity and that TLR4 plays a central role in the early host defense against infection. The results suggest that genetic variation of the TLR4 promoter is an essential, largely overlooked mechanism to influence TLR4 expression and UTI susceptibility. It was found that the protein expression was reduced and additionally the level of CXCR1 transcript and protein expression was lower in this new subset of pediatric patients. There is a great clinical need to identify genetic variants that improve resistance or increase susceptibility to infectious pathogens.

Citation: Ragnarsdóttir B, Svanborg C. 2012. Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection, p 358-378. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch21

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TLR4 is crucial for recognition of gram-negative bacteria and is best known as the LPS receptor. CD14 is a coreceptor for TLR4 and is essential for LPS recognition. Epithelial cells are, unlike macrophages and polymorphonuclear neutrophils, CD14 negative and as a result do not respond to LPS or commensal-like bacteria. However, epithelial cells respond in a pathogen-specific way and are activated by both P-and type 1-fimbriated but in different ways. P fimbriae bind to the Galα1-4Galb receptor epitope in the globoseries of glycosphingolipids (GSLs), resulting in ceramide release and activation of epithelial cells through a TLR4 and the TRIF/TRAM-dependent pathway. Type 1 fimbriae bind α-mannosylated glycoproteins (MGPs) and activate epithelial cells through TLR4 but through MyD88-dependent mechanisms. doi:10.1128/9781555817213.ch21f01

Citation: Ragnarsdóttir B, Svanborg C. 2012. Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection, p 358-378. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch21
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Three-generation pedigrees reveal a genetic predisposition to UTI. An accumulation of pyelonephritis was found in the relatives of the APN-prone patients (shown in red), while most of the UTI incidents in the control families were single episodes of cystitis (shown in gray), often associated with pregnancy. The arrows indicate the index APN-prone children. Partially reprinted from the ( ) with permission of the publisher. doi:10.1128/9781555817213.ch21f02

Citation: Ragnarsdóttir B, Svanborg C. 2012. Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection, p 358-378. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch21
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Some of the known TLR ligands (PAMPs)

Citation: Ragnarsdóttir B, Svanborg C. 2012. Host Genetic Variation, Innate Immunity, and Susceptibility to Urinary Tract Infection, p 358-378. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch21

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