Cutting Edge: <i>Tlr5</i>−/− Mice Are More Susceptible to <i>Escherichia coli</i> Urinary Tract Infection

Andersen‐Nissen, Erica; Hawn, Thomas R.; Smith, Kelly D.; Nachman, Alex; Lampano, Aaron E.; Uematsu, Satoshi; Akira, Shizuo; Aderem, Alan

doi:10.4049/jimmunol.178.8.4717

Cited by 174 publications

(146 citation statements)

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“…Because TLR5 is active when flagellin is administered i.n., we assume that apical/luminal signalling induces the epithelial response, as described previously [37]. It has been suggested that this type of epithelial innate mechanism is essential in mucosal defense against L. pneumophila, Pseudomonas aeruginosa and uropathogenic Escherichia coli [22,26,38]. Furthermore, respiratory pathogens that reach the basolateral side of the epithelial barrier via specific transport mechanisms or following trauma can stimulate either epithelial cells, airway smooth muscle, endothelial cells or any TLR5-expressing haematopoietic cells (such as lung macrophages and dendritic cells).…”

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“…A common stop codon polymorphism in TLR5 is associated to both increased susceptibility to pneumonia caused by the flagellated bacteria Legionella pneumophila and resistance to Crohn's disease, indicating that TLR5 signalling is relevant for mucosal immunity [20,21]. With TLR5-deficient mice, the critical role of TLR5 in mucosal inflammatory responses was established because deletion of Tlr5 gene alters response to respiratory, intestinal and urinary tract infections as well as mucosal homeostasis [1,[22][23][24][25][26]. Parenchyma and haematopoietic cells play a different role in TLR5-dependent mucosal immunity depending on the tissue studied.…”

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Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

et al. 2009

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Bacterial products (such as endotoxins and flagellin) trigger innate immune responses through TLRs. Flagellin-induced signalling involves TLR5 and MyD88 and, according to some reports, TLR4. Whereas epithelial and dendritic cells are stimulated by flagellin in vitro, the cell contribution to the in vivo response is still unclear. Here, we studied the respective roles of radioresistant and radiosensitive cells in flagellin-induced airway inflammation in mice. We found that i.n. delivery of flagellin elicits a transient change in respiratory function and an acute, pro-inflammatory response in the lungs, characterized by TLR5-and MyD88-dependent chemokine secretion and neutrophil recruitment. In contrast, TLR4, CD14 and TRIF were not essential for flagellin-mediated responses, indicating that TLR4 does not cooperate with TLR5 in the lungs. Respiratory function, chemokine secretion and airway infiltration by neutrophils were dependent on radioresistant, TLR5-expressing cells. Furthermore, lung haematopoietic cells also responded to flagellin by activating TNF-a production. We suggest that the radioresistant lung epithelial cells are essential for initiating early, TLR5-dependent signalling in response to flagellin and thus triggering the lung's innate immune responses.Key words: Chemokine . Epithelium . Flagellin . Lung inflammation . TLR5 IntroductionUpon challenge with respiratory pathogens, the airways rapidly develop a pro-inflammatory response initiated by environmental agents including microbe-associated molecular patterns such as Gram-negative bacteria LPS or endotoxins. This proinflammatory reaction plays an important role in the innate defense against respiratory pathogens [1,2]. Physiological changes induced by endotoxin inhalation include pulmonary Ã These authors contributed equally to this work. Eur. J. Immunol. 2009. 39: 1587-1596 DOI 10.1002 Innate immunity 1587 function and bronchoconstriction, cytokine and chemokine production, PMN recruitment, increased permeability of the alveolar epithelium and the associated endothelium [3][4][5][6]. TLR4 [7], together with MD-2, LPS-binding protein and CD14 detect endotoxins and play a critical role in the initiation of the pulmonary response to systemic and mucosal endotoxin administration [5,[8][9][10]. The pulmonary inflammation to endotoxin involves TLR4 signalling in both the parenchyma cells like endothelial and epithelial cells and the haematopoietic cells, i.e. monocytes, dendritic cells and neutrophils [11]. In addition, TLR4 signalling contributes to the development and progression of chronic respiratory disease including asthma [12][13][14][15][16].Flagellin is the major constituent of flagella from Gramnegative and Gram-positive bacteria. TLR5 has been identified as the main pattern recognition receptor required for flagellinmediated immune signalling [17]. TLR5 signalling depends on MyD88 and results in activation of MAPK, nuclear translocation of NF-kB and production of various pro-inflammatory cytokines and chemokines [18]. Moreover, a previous ...

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Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

et al. 2009

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“…Further research into the innate immune response may elucidate pathological mechanisms underlying infectious morbidities such as tubal infertility and preterm labour, but as yet few studies have examined the functional effects of innate immune components such as NAPs and TLRs in the reproductive tract. While existing SLPI (Ashcroft et al 2000) and TLRnull (Sugawara et al 2003, Andersen-Nissen et al 2007) mutant mouse models show impaired wound healing and altered responses to infection, they have provided little information relating directly to the reproductive tract. In addition, fundamental differences in key physiological reproductive processes, such as implantation and placentation, exist between mouse and human limiting the relevance of these rodent models.…”

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confidence: 99%

Innate immunity and disorders of the female reproductive tract

Horne¹,

Stock²,

King³

2008

Reproduction

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Sexually transmitted infections, and their associated sequelae, such as tubal infertility, ectopic pregnancy and preterm labour, are a major worldwide health problem. Chlamydia trachomatis infection is thought to be the leading global cause of tubal infertility and tubal ectopic pregnancy. Preterm birth occurs in around 10% of all deliveries, and nearly 30% of preterm deliveries are associated with intrauterine infection. The mucosal innate immune system of the female reproductive tract has evolved to eliminate such sexually transmitted pathogens whilst maintaining its ability to accommodate specialized physiological functions that include menstruation, fertilization, implantation, pregnancy and parturition. The aim of this review was to describe the role and distribution of key mediators of the innate immune system, the natural antimicrobial peptides (secretory leukocyte protease inhibitor, elafin and the defensins) and the pattern recognition toll-like receptors in the normal female reproductive tract and in the context of these pathological processes.

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“…In others, such as Salmonella enterica serovar Typhimurium, fliC is expressed during invasion through Peyer's Patches but not in the mesenteric lymph nodes or spleen to promote escape from immune responses and to spread to systemic sites of replication (10). Because much attention has been focused on immune recognition of bacterial flagellin via Toll-like receptor 5 (11)(12)(13), and it is unknown how flagella contribute to ascending infections, it would be advantageous to assess the spatial and temporal expression of UPEC flagellin in real time during UTI. Noninvasive biophotonic imaging has been used for real-time monitoring of organism density and spread in various animal models of infection, including UTI caused by Pseudomonas aeruginosa and Proteus mirabilis (14)(15)(16).…”

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Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract

Lane

Alteri

Smith

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Uropathogenic Escherichia coli (UPEC) cause most uncomplicated urinary tract infections (UTIs) in humans. Because UTIs are considered to occur in an ascending manner, flagellum-mediated motility has been suggested to contribute to virulence by enabling UPEC to disseminate to the upper urinary tract. Previous studies from our laboratory and others have demonstrated a modest yet important role for flagella during ascending UTI. To better understand the role of flagella in vivo, we used biophotonic imaging to monitor UPEC infection and temporospatial flagellin gene expression during ascending UTI. Using em7-lux (constitutive) and fliC-lux transcriptional fusions, we show that flagellin expression by UPEC coincides with ascension of the ureters and colonization of the kidney. The patterns of fliC luminescence observed in vitro and in vivo were also validated by comparative quantitative PCR. Because fliC expression appeared coincident during ascension, we reassessed the contribution of fliC to ascending UTI using a low-dose intraurethral model of ascending UTI. Although wild-type UPEC were able to establish infection in the bladder and kidneys by 6 hours postinoculation, fliC mutant bacteria were able to colonize the bladder but were significantly attenuated in the kidneys at this early time point. By 48 hours postinoculation, the fliC mutant bacteria were attenuated in the bladder and kidneys and were not detectable in the spleen. These data provide compelling evidence that wild-type UPEC express flagellin and presumably utilize flagellum-mediated motility during UTI to ascend to the upper urinary tract and disseminate within the host.biophotonic imaging ͉ urinary tract infection ͉ pyelonephritis ͉ motility ͉ fliC I t has been hypothesized that flagella, organelles required for motility, facilitate the establishment and spread of infection by microbial pathogens within the host (1, 2). Studies suggest that up to 95% of urinary tract infections (UTIs) develop in an ascending manner (3) beginning with periurethral colonization by bacteria such as uropathogenic Escherichia coli (UPEC), followed by migration to the bladder to establish infection, and if left untreated, ascension to the upper urinary tract or ureters and kidneys (4). Once in the kidneys, UPEC can gain access to the bloodstream, causing bacteremia and sometimes death (5). Because UTIs caused by UPEC are ascending infections involving multiple organs, we reasoned that monitoring flagella expression during UTI in real time would be useful as a model system to examine the connection between motility and the establishment and spread of bacterial infection.The bacterial flagellum is a long helical surface appendage composed of polymerized subunits of flagellin encoded by fliC. Mutation of fliC in UPEC leads to loss of flagellation and motility. Recently, our laboratory and others showed that fliC mutants were out-competed by motile wild-type strains during experimental cochallenge of mice, demonstrating that flagella contribute to the efficient colonization of...

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Cutting Edge: Tlr5−/− Mice Are More Susceptible to Escherichia coli Urinary Tract Infection

Cited by 174 publications

References 31 publications

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin

Innate immunity and disorders of the female reproductive tract

Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract

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