12 European Journal of Clinical Investigation Vol 38 DOI: 10.1111/j.1365-2362.2008.02004.x Blackwell Publishing Ltd ORIGINAL ARTICLES GENETICS OF UTI GENETICS OF UTI B. RAGNARSDÓTTIR ET AL. REVIEW ARTICLE TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections B. Ragnarsdóttir, H. Fischer, G. Godaly, J. Grönberg-Hernandez, M. Gustafsson, D. Karpman, A. C. Lundstedt, N. Lutay, S. Rämisch, M. L. Svensson, B. Wullt, M. Yadav and C. Svanborg Lund University, Sweden ABSTRACT The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger ‘pathogen-specific’ TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling. Keywords Innate immunity, Toll-like receptor 4, CXCR1, asymptomatic bacteriuria, acute pyelonephritis, ceramide signalling. Eur J Clin Invest 2008; 38 (S2): 12–20 Introduction Urinary tract infections (UTIs) are prevalent in all age groups and remain an essential cause of morbidity and mortality [1]. In addition, UTIs are a useful model to study pathogen specific activation of the innate host response and mechanisms of bacterial clearance [2]. After invasion of the sterile urinary tract, Escherichia coli and other uropathogens may either establish a state of commensalism or cause severe, symptomatic disease (Fig. 1). The virulent strains break the inertia of the mucosal barrier and may cause acute pyelonephritis, characterised by a rapid innate host response with cytokine secretion, and rapid recruitment of immune cells to the site of infection, which may lead to successful elimination of bacteria or to disease and tissue damage [3]. Asymptomatic bacteriuria (ABU) occurs, on the other hand, in at least 1% of the population and E. coli (> 10 5 cfu mL −1 ) may persist for months or years without evoking a destructive mucosal host response [4,5]. The mucosal immune system responds to invading pathogens with a vigorous antibacterial defence and yet these sites allow less virulent bacteria to establish an asymptomatic carrier state. Disease severity is determined by the balance between the pathogen and the host. Recent experimental studies of innate immunity have made it possible to identify genetic defects that increase the susceptibility to both symptomatic and asymptomatic UTI in patients and animal models [6–9]. The UTI severity also reflects the properties of the infecting strain and studies over several decades have identified crucial virulence factors among uropathogenic E. coli (UPEC) [10–13]. The ABU strains, in contrast, often fail to express those virulence factors, and recent studies have suggested that many ABU strains are attenuated UPEC strains [14–16]. The urinary tract relies on innate defence mechanisms for its antibacterial defence. Toll like receptors (TLRs) determine the efficiency of pathogen recognition while chemokine receptors (like CXCR1) are critical for bacterial clearance. Here we review mechanisms of pathogen specific TLR4 activation based on co-receptors for pathogen specific ligands and adaptor protein