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NDT Advance Access originally published online on October 11, 2006
Nephrology Dialysis Transplantation 2007 22(2):347-349; doi:10.1093/ndt/gfl590
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Uncovering host defences in the urinary tract: cathelicidin and beyond*

Marcus D. Säemann, Walter H. Hörl and Thomas Weichhart

Department of Internal Medicine III, Clinical Division of Nephrology & Dialysis, Medical University of Vienna, Austria

Correspondence and offprint requests to: Marcus D. Säemann, Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Email: marcus.saemann{at}meduniwien.ac.at

Keywords: antimicrobial; innate immunity; neutrophils; toll-like receptors; urinary tract infection

While typical mucosal tissues like the gut are faced with a huge number of commensal and pathogenic micro-organisms, the urinary tract is largely "microbiologically naïve". Interestingly, the urogenital tract is devoid of a variety of physically acting countermechanisms like a multilayered mucus or ciliated epithelium and therefore, specific host strategies to avoid infection of the urinary tract have been proposed [1]. Nevertheless, invasion of uropathogenic bacteria leading to urinary tract infection (UTI), is a major health problem affecting millions of people every year with a tremendous economic impact and might in the worst case lead to kidney damage in terms of chronic renal failure [2,3]. During evolution, distinct uropathogenic microbes predominantly derived from the gut microflora, have developed potent strategies to undermine the urogenital immune defence [4]. In recent years important advances in our understanding of the molecular mechanisms governing host resistance and in maintaining tissue homeostasis in the urinary tract to ultimately prevent constant microbial invasion have been made. The discovery of toll-like receptors (TLRs), distinct pathogen recognition receptors linking microbe recognition with immune cell activation, has extended our view on the principles governing host–microbial relationship in the urinary tract [5,6]. TLRs, when engaged by peculiar microbial molecules such as lipopolysaccharide (LPS), which is recognized among other co-receptors by TLR4, lead to activation of a specific intracellular signalling cascade finally activating the production of an array of inflammatory cytokines and chemokines in innate immune and also uroepithelial cells. Uropathogenic in contrast to commensal bacteria employ specific attachment structures like type-1 and P fimbriae to firmly bind to uroepthelial cells, which enables them to invade the mucosal tissue. Interestingly, the urogenital epithelium reacts against microbials and their surface molecules like LPS via TLR4 only in conjunction with specific receptors recognizing pathogenic type-1 or P fimbriae, thereby discriminating between pathogens and commensals, while innate immune cells are activated by the mere presence of LPS [7]. Mechanistically, this is attributed to the LPS-coreceptor CD14, which is present on innate immune cells but is lacking on the urogenital epithelium providing an intriguing example for a differential sensitivity pattern for microbes depending on tissue localization.

Previous work has contributed considerable data to a scenario that places epithelial cells in the centre of the urinary defence system, since they constitute the first line of defence when encountering uropathogenic bacteria such as Escherichia coli (Figure 1). After adherence to the uroepithelium via their fimbriae, which is the rate-limiting step during UTI, the invading bacteria may reside within the epithelium for years and thereby contribute to silent or chronic infection as well as to repeated bouts of acute infection due to subverting the immune response in genetically and environmentally susceptible hosts [8]. Alternatively, in individuals, who do not develop chronic UTI, an initial proper alert may lead to a sufficiently rapid immune cell activation culminating in the final clearance of the bacteria from the organism. Between these opposing outcomes, different factors that either prevent further bacterial colonization once they have attached and that activate epithelial and immunocompetent cell, signalling pathway, are operative. Hence, an orchestrated response by TLRs, cytokines, chemokines, antimicrobial as well as hitherto undefined molecules is essential to eliminate danger from the host. For example, Tamm–Horsfall Protein (THP), which is selectively produced by the thick ascending limb of Henle and shed into the urine, has recently been found to behave as a multilayered defence molecule. THP contributes to bacterial elimination from a mechanistic point of view by adhering to specific mannosylated residues on uropathogenic bacterial fimbriae preventing attachment and thus promoting bacterial urinary wash-out [9,10]. Moreover, THP has an immunomodulatory role by activating innate immune cells such as dendritic cells via a TLR4-dependent mechanism to lower the activation threshold against THP-bound uropathogenic bacteria [11,12]. A similar dual function was previously described for ß-defensins produced by various epithelial cells and which possess direct antimicrobial activity, but may also activate immune effector functions via a TLR-dependent machinery [13,14].


Figure 1
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  		Fig. 1. Multilayered effector mechanisms to combat UTI. Soluble factors like low molecular weight sugars, Tamm–Horsfall protein or secretory IgA inhibit attachment of uropathogenic E. coli (UPEC) to the epithelium. Despite these defence mechanisms, some bacteria are able to attach and invade the epithelium, which in turn releases antimicrobial molecules like cathelicidin, defensins or nitric oxide. Moreover, the uroepithelium produces IL-6 and IL-8 to attract additional immunocompetent cells like neutrophils, which help to eliminate the pathogens. However, recent data including the results from Chromek et al. [15] indicate that neutrophil-derived molecules such as cathelicidin might contribute to systemic immunopathology and damage to the host.

 
Furthermore, investigation into the host–microbial interaction in the urinary tract might not only reveal successful defence strategies of the host but may shed some further light on the associated genes that underlie disease susceptibility e.g. for recurrent UTIs. Chromek et al. recently discovered the function of the antimicrobial peptide cathelicidin that serves to play an important role for maintaining the integrity of the urinary tract [15]. Cathelicidin belongs to one of the two main families of cationic antimicrobial peptides in humans besides defensins, and is also produced by innate immune cells like neutrophils and epithelial cells [16]. The cathelicidin gene, CAMP, is translated into the propeptide pro-LL-37 and extracellularly cleaved into cathelin and LL-37, both of which possess complementary antimicrobial effects. A previous finding that cathelicidins destroy uropathogenic bacteria rather than urinary commensals led to the hypothesis of Chromek et al. that cathelicidins might be essential for the local urinary tract milieu [17]. A first clue to this function was the association of severe forms of UTI such as pyelonephritis in children with highly increased levels of urinary cathelicidin. Further experimental analysis revealed that several epithelial cells and also resident renal tubular cells did not produce significant amounts of the propeptide, but rapidly started to express and secrete cathelicidin upon experimental bacterial infection. Indeed, peptide secretion was observed as early as 5 min after stimulation suggesting an activation-induced release from preformed granules, a mechanism known from previous studies [18]. Upon UTI, Camp–/– mice exhibited significantly more E. coli attached to the epithelium, displayed severe signs of disease and finally demonstrated an increased incidence of mortality due to septicaemia. Intriguingly, E. coli strains associated with clinically more severe courses of UTI were rather resistant towards the bactericidal effects of cathelicidins.

Neutrophil recruitment has been shown to be critical for bacterial clearance from both the bladder and kidney, and the presence of neutrophils in the urine is a hallmark of UTI [8]. Since a main source of cathelicidin secretion (besides epithelial cells) were neutrophils in their experiments, the authors depleted these cell populations with selective antibodies to discern the relative contribution of the epithelial cells for the antibacterial response. Interestingly, the infection rate of challenged mice was not influenced by neutrophil depletion, indicating that neutrophils and neutrophil-produced cathelicidin in contrast to epithelial cell-derived cathelicidin, are not critical in their experimental model. Rather, neutrophils were responsible for the clinical severity of the UTI (Figure 1). Therefore, these data suggest that at least the epithelial cell-derived cathelicidin is a primary preventive factor against microbial invasion. Clearly, further work is required to uncover the role of cathelicidin production by neutrophils in the context of urogenital tract homeostasis.

The data by Chromek et al. [15] lend additional support to the idea that the welfare of the urogenital tract system is profoundly dependent on specific soluble epithelial cell-derived mediators that have evolved upon microbial pressure to selectively combat uropathogenic bacteria. Interestingly, most of these recently identified molecules such as ß-defensins, cathelicidins, or THP exert multiple effector functions apart from mechanical elimination of bacteria. Hence, directing immune cell recruitment by these regulatory molecules not only contributes to an additional layer of complexity in the general defence structure, but also offers an additional explanation for the individual reactivity pattern, which may range from asymptomatic bacteriuria to the harmful destruction of the renal parenchyma. As distinct immune cell genes such as the IL-8R or chemokine receptor CXCR1, which activate and efficiently direct neutrophils, have been shown to be associated with UTI susceptibility, elucidation of novel antibacterial molecules also holds the promise of having a strong impact not only on novel genetic susceptibility regions, but also on translation into novel treatment options for patients suffering from recurrent UTI is possible.

Conflict of interest statement. None declared.



   Notes
 
* Comment on Chromek M, Slamova Z, Bergman P et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 2006; 12: 636–641. Back



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