Deepak S. Ipe
Ella Horton
Glen C. Ulett- School of Medical Science, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia
Bacteriuria, the presence of bacteria in urine, is associated with asymptomatic, as well as symptomatic, urinary tract infection (UTI). Bacteriuria underpins some of the dynamics of microbial colonization of the urinary tract, and probably impacts the progression and persistence of infection in some individuals. Recent molecular discoveries in vitro have elucidated how some key bacterial traits can enable organisms to survive and grow in human urine as a means of microbial fitness adaptation for UTI. Several microbial characteristics that confer bacteruric potential have been identified including de novo synthesis of guanine, relative resistance to D-serine, and catabolism of malic acid. Microbial characteristics such as these are increasingly being defined through the use of synthetic human urine (SHU) in vitro as a model to mimic the in vivo environment that bacteria encounter in the bladder. There is considerable variation in the SHU model systems that have been used to study bacteriuria to date, and this influences the utility of these models. In this review, we discuss recent advances in our understanding of bacteruric potential with a focus on the specific mechanisms underlying traits that promote the growth of bacteria in urine. We also review the application of SHU in research studies modeling UTI and discuss the chemical makeup, and benefits and limitations that are encountered in utilizing SHU to study bacterial growth in urine in vitro.
Introduction: Bacteriuria and Urinary Tract Infection
“Asymptomatic Bacteriuria” (ABU or ASB) is synonymous with asymptomatic Urinary Tract Infection (UTI) in defining the isolation of a specified semi-quantitative count of bacteria in an appropriately collected urine specimen from a person without signs or symptoms related to UTI (Rubin et al., 1992; Nicolle et al., 2005). Bacteriuria is a marker for symptomatic UTI (sUTI) and assists in grading the severity of infection. Establishment of bacteriuria depends on entry of an organism with bacteruric potential into the urinary tract and can persist for months or years. Bacteruric potential encompasses microbial survival, growth, and re-growth in urine, and endurance of host defense mechanisms including dilution, voiding, frequent flushing (O'grady and Cattell, 1966a,b), and antimicrobial constituents such as Tamm-Horsfall glycoprotein (aka uromodulin), and P blood group antigen (Hand et al., 1971; Lomberg et al., 1983; Bates et al., 2004). Bacteruric potential can thus influence the persistence of ABU and sUTI. Here, we analyze the differences in microbial strategies used for growth in urine and the methods for modeling bacteriuria using synthetic human urine (SHU).
Microbial Bacteruric Potential and Host Dynamics
Recent reviews have focused on the pathogenesis of acute sUTI (Nielubowicz and Mobley, 2010; Hannan et al., 2012; Ulett et al., 2013), and ABU (Ipe et al., 2013; Schneeberger et al., 2014) and will not be revisited here. We will focus on bacteriuria specifically; the progression of which depends on microbe traits as well as host factors. Most individuals who suffer persistent UTI do not harbor the same strain of organism over time (Hooton et al., 2000), implying that turnover of causal organisms is dynamic. Replacement of colonizing strains during bacteriuria has been studied for Escherichia coli, the most common cause of ABU (Ipe et al., 2013). Long-term bacteriuria appears to select for attenuated virulence phenotypes of colonizing strains (Salvador et al., 2012). While most microbes are killed by urine, different organisms have distinct bacteruric potential. Several traits can affect microbial growth in urine. Antibiotics stop the progression of bacteriuria (Schneeberger et al., 2012) but patients infected with E. coli experience re-colonization with the same or similar organism at high rates (Dalal et al., 2009). This highlights the dynamic nature of bacteriuria and the role of therapeutic intervention [that is not recommended as routine for ABU (Nicolle, 2014)]. Other factors that are associated with the promotion of long-term bacteriuria are defects in immune signaling pathways such as TLRs (Ragnarsdóttir and Svanborg, 2012). Thus, persistence of bacteriuria relates to microbial bacteruric potential and host characteristics/dynamics including genetic immunodeficiency, re-current infection or strain replacement, and antibiotic therapy.
Microbial Metabolism and Growth Fitness in Urine: Knowledge from E. coli
The progression of bacteriuria depends on a microbes' ability to survive the antimicrobial properties of urine. Urine survival and growth maintains a pool of colonizing organisms regardless of adherence to host cells, and urodynamic properties (urine flow rates, voiding) that differ between individuals (Wullt et al., 1998). Non-voided organisms in residual urine can grow and re-grow to maintain infection. Discoveries using ABU microbes have shaped our understanding of how bacteriuria progresses. ABU E. coli strain 83972 displays robust fitness for urine growth (Klemm et al., 2006; Roos et al., 2006b) though this is not a defining feature of all ABU E. coli, and is observed in some uropathogenic E. coli (UPEC) (Stamey and Mihara, 1980; Alteri and Mobley, 2007; Alteri et al., 2009; Aubron et al., 2012). Poor urine growth has been reported for some fecal E. coli isolates (Stamey and Mihara, 1980; Gordon and Riley, 1992). ABU E. coli 83972 has been investigated as a prophylactic means to treat acute sUTI (Hull et al., 2000; Wullt, 2003; Roos et al., 2006a; Sundén et al., 2006; Klemm et al., 2007; Watts et al., 2012a). The metabolic basis for urine growth of ABU E. coli 83972 involves transport and degradation pathways for galacturonate, glucuronide and galactonate (Roos et al., 2006b), and antioxidant defense mechanisms (Aubron et al., 2012); the details are described elsewhere (Roos et al., 2006a,b). More recently, analysis of ABU E. coli 83972 re-isolates indicated marked versatility of metabolic pathways in urine, including utilization of amino acids, hexuronates or (deoxy-) ribonucleosides as an adaptation to individual hosts (Zdziarski et al., 2010). This underlines the metabolic versatility of E. coli in urine in response to host-specific metabolic constraints. guaA and argC were shown to be critical for urine growth and a lack of urinary guanine (or derivatives), combined with an inability of E. coli to synthesize these compounds de novo, prevents the synthesis of other guanine (or derivative)-dependent products that are required for growth (Russo et al., 1996). Separate from guanine, argC and carAB mutants had reduced growth in urine in a E. coli transposon mutagenesis study, illustrating a role for arginine metabolism (Vejborg et al., 2012).
Knowledge from Bacteria other than E. coli
Clinical isolates of Enterococcus faecalis, Proteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus saprophyticus, and Streptococcus agalactiae have been shown to grow in human urine (Table 1). However, little is known about the mechanisms used by these organisms for urine growth. For E. faecalis there are some similarities to E. coli; E. faecalis expresses multiple virulence genes in urine (Shepard and Gilmore, 2002) including genes for iron transport (Vebø et al., 2010). Iron utilization mechanisms have been reported in urine growth assays with E. coli (Watts et al., 2012b). Limiting manganese may be important in restricting E. faecalis urine growth (Järvisalo et al., 1992; Low et al., 2003; Vebø et al., 2010). In contrast to activation of pathways described for E. coli, E. faecalis activates citrate and aspartate metabolic pathways, and represses glucose uptake (Vebø et al., 2010). Human urine contains more citrate than glucose (Shaykhutdinov et al., 2009; Wishart et al., 2009; Bouatra et al., 2013), which could promote growth of E. faecalis. However, human urine is highly variable in chemical constituency and different levels of components such as glucose may influence microbial growth; for example, glucosuria enhances growth of E. coli. E. faecalis also upregulates genes for utilization of sucrose (and perhaps fructose), another constituent of urine (Tasevska et al., 2005; Bouatra et al., 2013). Other E. faecalis genes thought to function in urine growth include those related to import of phosphorylated sugars and glycerol, N-acetyl glucosamine metabolism (Vebø et al., 2010), cysteine synthase, and pathways for conversion of aspartate and α-ketoglutarate to oxaloacetate and glutamate. Urinary aspartate may be used for nitrogen metabolism (Guo and Li, 2009). E. faecalis is auxotrophic for multiple amino acids but human urine contains several amino acids including arginine, glutamate, glycine, and leucine (Guo and Li, 2009; Bouatra et al., 2013).
Table 1. Summary of traits that contribute to bacteruric potential in microbes.
An analysis of metabolic traits of P. aeruginosa using synthetic urine revealed adaptation in central metabolism to lactate, citrate, and amino acids as carbon sources, and the induction of amino acid utilization pathways (Tielen et al., 2013). Metabolic flux analysis showed the use of the Entner-Doudoroff pathway with respiratory metabolism, with the pentose phosphate pathway being used exclusively for biosynthesis. Flux through pyruvate metabolism, the tricarboxylic acid cycle, and the glyoxylate shunt was highly variable, and likely caused by adaptive processes in individual strains during infection (Berger et al., 2014).
Phenotype metabolic arrays were recently reported for ABU S. agalactiae (Ipe et al., 2016). Comparison with S. agalactiae strains that were unable to grow in urine showed that malic acid catabolism was important for growth in urine. Malic acid utilization is related to the malic enzyme metabolic pathway that catalyzes the oxidative decarboxylation of malate (a component of human urine depending on diet) to pyruvate and CO2. This is related to malolactic fermentation, a bacterial metabolic process typically associated with wine deacidification (Landete et al., 2010).
Three Ways to Survive in Urine: Resistance, Acquisition, and Osmoadaption
Urine is naturally antimicrobial; hypertonicity with low pH (averaging ~6.0) and high concentrations of urea inhibit most bacteria (Chambers and Lever, 1996; Kucheria et al., 2005). Nitrite in mildly acidified urine inhibits the growth of some uropathogens (Carlsson et al., 2001), and other abundant proteins such as Tamm-Horsfall glycoprotein are antimicrobial (Raffi et al., 2005; Säemann et al., 2005). Recently, the antimicrobial properties of urine were shown to include specific inhibition of both expression and function of UPEC type 1 pili (Greene et al., 2015), and downregulation of capsule genes (King et al., 2015). Individualistic urinary chemical features can also affect the antimicrobial properties of some antimicrobial urinary proteins such as siderocalin (Shields-Cutler et al., 2015). Bacteria that can endure urine antimicrobial properties do so through various means; for example, S. saprophyticus tolerates high concentrations of D-serine, which is abundant in urine and bacteriostatic toward organisms that lack a D-serine deaminase (Cosloy and McFall, 1973; Hryckowian et al., 2015). Iron limitation and the presence iron chelators such as lactoferrin (Weinberg, 1978) compounds the problem of nutritional immunity for microbes (Hood and Skaar, 2012) especially during states of increased iron chelator production (Gonzalez-Chavez et al., 2009; Soler-García et al., 2009). Siderophores confer bacteruric potential to E. coli (Håversen et al., 2000; Snyder et al., 2004; Alteri and Mobley, 2007; Hagan and Mobley, 2009; Garcia et al., 2011; Watts et al., 2012b) and several genes encoding factors involved in iron transport are upregulated in E. faecalis during urine growth (Vebø et al., 2010). Siderophores may also act as ligands for cations other than iron, such as copper (Chaturvedi et al., 2012). Variable resistance to urinary defense molecules (e.g., nitrite, ascorbic acid) could influence bacteruric potential but little is known beyond the effects of these toward the chemical properties of urine (Carlsson et al., 2001). Finally, many organisms are probably unable to survive the oxygen concentrations encountered in the bladder (Leonhardt and Landes, 1963; Clarke et al., 1985).
Urea is abundant in urine and is antibacterial (Sobel, 1985). Osmoadaptive systems enable some bacteria to survive the stressful hypertonic conditions of urine. Bacterial accumulation of osmotically compatible solutes that are present in urine (e.g., betaines) confers bacteruric potential by effectively enabling microbes to resist dehydration (Chambers and Lever, 1996; Deutch et al., 2006). Osmoadaptive systems respond to changes in tonicity in urine, and support survival by counteracting low pH, high urea concentrations and hypertonicity (Chambers and Lever, 1996). For E. coli, glycine betaine is a central osmoprotectant to resist urea toxicity, and its accumulation is essential to adaptive responses to osmotic stress (Kunin et al., 1992; Chambers and Lever, 1996). E. coli increases the activity of potassium transport systems that encompass TrkG, TrkH, and Kup (Meury et al., 1985), or Kdp (Laimins et al., 1978) to counteract osmotic stress. Other systems involve trehalose as an organic osmolyte; its induction is triggered in conditions of high potassium (and glutamate) (Strøm and Kaasen, 1993), and its accumulation elicits the release of potassium from the cell (Dinnbier et al., 1988). This might aid growth since trehalose can be used as a carbon source (Gutierrez et al., 1989; Styrvold and Strøm, 1991). OmpR regulates osmoadaptive genes in E. coli (Barron et al., 1986). Osmotic stress suppresses the expression of fimbriae and flagellin (Kunin et al., 1994, 1995). Future studies of bacteria other than E. coli that can grow in urine will elucidate additional mechanisms of resistance to urinary antimicrobial properties, nutrient acquisition and metabolism, and osmoadaption.
Between a Rock and a Hard-Place: The Bladder Mucosa-Lumen Interface of Immune Surveillance and Bacteriuria
Inflammation is a critical part of sUTI pathogenesis (Hannan et al., 2012; Ulett et al., 2013) and involves thousands of genes that drive antibacterial responses within hours of infection (Duell et al., 2012; Tan et al., 2012; Carey et al., 2016). For example, antimicrobial peptides produced by the bladder are important for protection against infection (Chromek et al., 2006). Microbes must survive these inflammatory events. Urine is a “Hard-place” for microbes to survive, as discussed above. Tissue inflammation in the bladder represents a “rock” of antimicrobial responses for defense against UTI and, for ABU, can encompass pyuria, cytokine release (IL-1α, -6, and -8), and antibody production, which has been documented in elderly adults, as reviewed elsewhere (Nicolle, 1997). Excessive inflammation may contribute to chronic sUTI (Hannan et al., 2010) and some acute sUTI symptoms have been linked to specific inflammatory events (Rudick et al., 2010). However, the benign, minimally inflammatory nature of ABU is reflected in the lack of morbidity in individuals who do not receive therapy (Nicolle, 1997, 1999; Ariathianto, 2011). Details of how ABU bacteria induce and minimize inflammation offer insight into how microbial modulation of host defense may promote bacteriuria. ABU E. coli minimizes inflammation by averting adherence due to a lack of fimbriae expression; this limits immune activation (Roos et al., 2006b) and results in long-term ABU (Arthur et al., 1989; Andersson et al., 1991). Grönberg-Hernandez et al. showed that ABU E. coli activates IRF3 and TLR4-dependent signaling, however, triggering a response that depends on host genetic background (Grönberg-Hernández et al., 2011); the IRF3-dependent signaling pathway is critical for distinguishing pathogens from the normal flora (Fischer et al., 2010). TLR4 senses P-fimbriated E. coli (Frendéus et al., 2001), and TLR4 mutations may favor ABU by impeding innate responses (Svanborg et al., 2006). This raises the question of whether ABU may influence subsequent encounter(s) with other uropathogens. One study on streptococcal UTI showed an influence on the severity of subsequent E. coli UTI in mice (Kline et al., 2012). Thus, immune activation triggered by ABU might affect subsequent sUTI caused by diverse pathogens. These data offer some parallel to clinical observations that patients with E. coli ABU suffer re-colonization at high rates following therapy (Dalal et al., 2009).
Modeling Bacteriuria In vitro: Synthetic Human Urine (SHU)
Urine is unique from a microbial perspective and its chemical makeup, distinct from all other bodily fluids, has been modeled for studying the growth of microbes for 50 years (O'grady and Pennington, 1966). Urine has a low pH and a high osmolality due to the presence of salts and urea (Kucheria et al., 2005; Sheewin, 2011). The peptides, proteins, and organic acids present in urine may be metabolized by microbes (Decramer et al., 2008). Urine is dynamic in flow rate and composition, which changes subject to diet, age, gender and health status, and disease. Decreased levels of THP, for example, are associated with diabetes (Torffvit and Agardh, 1993) and infection (Ronald and Ludwig, 2001). Data on microbial traits that afford bacteruric potential have, in many cases, been derived from studies using SHU. Eight original SHU media recipes were described between 1971 and 2010: as summarized according to research application and composition in Table 2.
Table 2. Original and subsequent studies using Synthetic Human Urine (SHU) (A), and related SHU constituents, and proposed composite SHU (B).
SHU offers several advantages compared to normal human urine collected from healthy adults for research assays ex vivo; it avoids the issue of variable chemical composition encountered with fresh human urine; variation in urinary constituents between individuals (Bouatra et al., 2013) is a challenge for standardizing research studies. Methods for “normalizing” fresh human urine include pooling samples and adjusting dilution/concentration according to creatinine concentration, specific gravity, and osmolality. The most widely used method is creatinine adjustment (Barr et al., 2005), however no bacteriuria research studies to date have applied these methods for normalizing, and the effects on data interpretation are unknown. Volume limits have been difficult for some studies (Davis et al., 1982). As a surrogate model, the benefits of SHU are defined by how closely it can reflect the chemical complexity of fresh human urine. Urine from a healthy adult contains glucose (0.2–0.6 mM) (Shaykhutdinov et al., 2009), creatine (0.38–55.6 mM; Barr et al., 2005; Shaykhutdinov et al., 2009), and glycine with low levels of other amino acids such as D-serine (Huang et al., 1998; Pätzold et al., 2005), histidine, glutamine, methionine, proline, glutamate, arginine, cysteine, and branched chain amino acids (Guo and Li, 2009; Vebø et al., 2010). It contains trace fatty acids, citrate (1.0–2.0 mM) (Wishart et al., 2009), sucrose (70–200 μM) (Tasevska et al., 2005), and manganese (nM range) (Järvisalo et al., 1992).
To standardize SHU composition for bacteriuria studies, we propose a composite SHU medium recipe (Table 2), and compare this to descriptions of “typical human urine” (Putnam et al., 1971; Bouatra et al., 2013). Examples of supplements to previously used SHU formulations include Lysogeny Broth (LB), Todd-Hewitt Broth (THB), and dextrose for fungi such as Candida sp. (Table 2). The proposed composite SHU medium omits chemically undefined components such as LB to provide chemical definition, is easily prepared, inexpensive, and chemically stable. However, it is also not without its limitations; it excludes some natural constituents of human urine such as hormones, iron chelators, and pyrophosphates that could influence microbial growth. The relative concentrations of some urinary constituents differ between males and females (e.g., less calcium and oxalate, more citrate excretion in women, more creatinine in men; Ryall et al., 1987; Sarada and Satyanarayana, 1991; Bouatra et al., 2013) and the proposed composite SHU does not account for these differences. Nonetheless, as a balance between feasibility, logistics, and economy the proposed composite SHU medium should be of value to standardize future bacteriuria studies; importantly, studies will now need to validate the proposed composite SHU medium using a range of relevant bacteria, and in particular, analyze the need for supplements (e.g., yeast extract) to support the growth of fastidious organisms such as streptococci.
Conclusions and Future Directions
A capacity of microorganisms for urine growth may aid in establishing long-term bacteriuria and is relevant to many microbial species. New discoveries on immune activation by ABU show this form of infection does not exist entirely under the radar of immune surveillance. Continued use of SHU for in vitro studies will drive new discoveries on how bacteriuria progresses and how this may influence subsequent infection. Future work needs to address multiple areas; including (1) validation of the proposed composite SHU medium using a range of relevant bacteria; (2) defining differences in “significant” bacteriuria for different organisms and the implications of bacteruric potential toward such definitions; (3) lifestyle adaptations, other than those described for D-serine, guanine, malic acid, and iron acquisition that aid microbial bacteruric potential; (4) the molecular basis of urine growth in non-E. coli organisms; how ABU interfaces with host immune mechanisms for different organisms (and among distinct patient populations); (5) differences in male vs. female urine composition, in particular hormones (and whether this influences bacterial growth); and (6) how ABU impacts on subsequent UTI including comparisons of immune responses to ABU caused by organisms other than E. coli. How effective ABU might be as a prophylactic approach against sUTI continues to be a topic for future investigation. More importantly, studies aimed at defining bacterial mechanisms that are critical for growth in urine are essential in the context of providing a foundation for novel treatment and preventive strategies.
Author Contributions
DI, EH, and GU conceived of the study, analyzed the literature, and wrote the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
This work was supported by an Australian National Health and Medical Research Council (NHMRC) grant (APP1084889) (GU), and a Griffith University New Researcher Grant (219152) (DI). GU is supported by a Future Fellowship from the Australian Research Council (FT110101048).
References
Alteri, C. J., and Mobley, H. L. (2007). Quantitative profile of the uropathogenic Escherichia coli outer membrane proteome during growth in human urine. Infect. Immun. 75, 2679–2688. doi: 10.1128/IAI.00076-06
Alteri, C. J., Smith, S. N., and Mobley, H. L. (2009). Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle. PLoS Pathog. 5:e1000448. doi: 10.1371/journal.ppat.1000448
Andersson, P., Engberg, I., Lidin-Janson, G., Lincoln, K., Hull, R., Hull, S., et al. (1991). Persistence of Escherichia coli bacteriuria is not determined by bacterial adherence. Infect. Immun. 59, 2915–2921.
Ariathianto, Y. (2011). Asymptomatic bacteriuria - prevalence in the elderly population. Aust. Fam. Physician 40, 805–809.
Arthur, M., Johnson, C. E., Rubin, R. H., Arbeit, R. D., Campanelli, C., Kim, C., et al. (1989). Molecular epidemiology of adhesin and hemolysin virulence factors among uropathogenic Escherichia coli. Infect. Immun. 57, 303–313.
Aubron, C., Glodt, J., Matar, C., Huet, O., Borderie, D., Dobrindt, U., et al. (2012). Variation in endogenous oxidative stress in Escherichia coli natural isolates during growth in urine. BMC Microbiol. 12:120. doi: 10.1186/1471-2180-12-120
Aurora, A. L., Rao, A. S., and Srimathi, V. (1980). Effects of constituents of artificial urine on spontaneous precipitation of calcium oxalate monohydrate (whewellite). Ind. J. Med. Res. 72, 273–283.
Azevedo, A. S., Almeida, C., Melo, L. F., and Azevedo, N. F. (2014). Interaction between atypical microorganisms and E. coli in catheter-associated urinary tract biofilms. Biofouling 30, 893–902. doi: 10.1080/08927014.2014.944173
Barker, L. M., Pallante, S. L., Eisenberg, H., Joule, J. A., Becker, G. L., and Howard, J. E. (1974). Simple synthetic and natural urines have equivalent anticalcifying properties. Invest. Urol. 12, 79–81.
Barr, D. B., Wilder, L. C., Caudill, S. P., Gonzalez, A. J., Needham, L. L., and Pirkle, J. L. (2005). Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ. Health Perspect. 113, 192–200. doi: 10.1289/ehp.7337
Barron, A., May, G., Bremer, E., and Villarejo, M. (1986). Regulation of envelope protein composition during adaptation to osmotic stress in Escherichia coli. J. Bacteriol. 167, 433–438.
Bates, J. M., Raffi, H. M., Prasadan, K., Mascarenhas, R., Laszik, Z., Maeda, N., et al. (2004). Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 65, 791–797. doi: 10.1111/j.1523-1755.2004.00452.x
Berger, A., Dohnt, K., Tielen, P., Jahn, D., Becker, J., and Wittmann, C. (2014). Robustness and plasticity of metabolic pathway flux among uropathogenic isolates of Pseudomonas aeruginosa. PLoS ONE 9:e88368. doi: 10.1371/journal.pone.0088368
Bouatra, S., Aziat, F., Mandal, R., Guo, A. C., Wilson, M. R., Knox, C., et al. (2013). The human urine metabolome. PLoS ONE 8:e73076. doi: 10.1371/journal.pone.0073076
Brooks, T., and Keevil, C. W. (1997). A simple artificial urine for the growth of urinary pathogens. Lett. Appl. Microbiol. 24, 203–206. doi: 10.1046/j.1472-765X.1997.00378.x
Brown, P., Ackermann, D., and Finlayson, B. (1989). Calcium-Oxalate Dihydrate (Weddellite) Precipitation. J. Cryst. Growth 98, 285–292. doi: 10.1016/0022-0248(89)90143-7
Burns, J. R., and Finlayson, B. (1980). A proposal for a standard reference artificial urine in in vitro urolithiasis experiments. Invest. Urol. 18, 167–169.
Carey, A. J., Sullivan, M. J., Duell, B. L., Crossman, D. K., Chattopadhyay, D., Brooks, A. J., et al. (2016). Uropathogenic Escherichia coli engages CD14-dependent signaling to enable bladder-macrophage-dependent control of acute urinary tract infection. J. Infect. Dis. 213, 659–668. doi: 10.1093/infdis/jiv424
Carlsson, S., Wiklund, N. P., Engstrand, L., Weitzberg, E., and Lundberg, J. O. (2001). Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide 5, 580–586. doi: 10.1006/niox.2001.0371
Chambers, S. T., and Lever, M. (1996). Betaines and urinary tract infections. Nephron 74, 1–10. doi: 10.1159/000189274
Chaturvedi, K. S., Hung, C. S., Crowley, J. R., Stapleton, A. E., and Henderson, J. P. (2012). The siderophore yersiniabactin binds copper to protect pathogens during infection. Nat. Chem. Biol. 8, 731–736. doi: 10.1038/nchembio.1020
Christmas, K. G., Gower, L. B., Khan, S. R., and El-Shall, H. (2002). Aggregation and dispersion characteristics of calcium oxalate monohydrate: effect of urinary species. J. Colloid Interface Sci. 256, 168–174. doi: 10.1006/jcis.2002.8283
Chromek, M., Slamová, Z., Bergman, P., Kovács, L., Podracká, L., Ehrén, I., et al. (2006). The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641. doi: 10.1038/nm1407
Chutipongtanate, S., and Thongboonkerd, V. (2010). Systematic comparisons of artificial urine formulas for in vitro cellular study. Anal. Biochem. 402, 110–112. doi: 10.1016/j.ab.2010.03.031
Clarke, M., Pead, L., and Maskell, R. (1985). Urinary infection in adult men: a laboratory perspective. Br. J. Urol. 57, 222–226. doi: 10.1111/j.1464-410X.1985.tb06429.x
Cosloy, S. D., and McFall, E. (1973). Metabolism of D-serine in Escherichia coli K-12: mechanism of growth inhibition. J. Bacteriol. 114, 685–694.
Dalal, S., Nicolle, L., Marrs, C. F., Zhang, L., Harding, G., and Foxman, B. (2009). Long-term Escherichia coli asymptomatic bacteriuria among women with diabetes mellitus. Clin. Infect. Dis. 49, 491–497. doi: 10.1086/600883
Dalhoff, A., Stubbings, W., and Schubert, S. (2011). Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine. Antimicrob. Agents Chemother. 55, 1814–1818. doi: 10.1128/AAC.00886-10
Darouiche, R. O., Mansouri, M. D., Gawande, P. V., and Madhyastha, S. (2008). Efficacy of combination of chlorhexidine and protamine sulphate against device-associated pathogens. J. Antimicrob. Chemother. 61, 651–657. doi: 10.1093/jac/dkn006
Davis, C. P., Arnett, D., and Warren, M. M. (1982). Iontophoretic killing of Escherichia coli in static fluid and in a model catheter system. J. Clin. Microbiol. 15, 891–894.
Davis, C. P., Wagle, N., Anderson, M. D., and Warren, M. M. (1991). Bacterial and fungal killing by iontophoresis with long-lived electrodes. Antimicrob. Agents Chemother. 35, 2131–2134. doi: 10.1128/AAC.35.10.2131
Davis, C. P., Weinberg, S., Anderson, M. D., Rao, G. M., and Warren, M. M. (1989). Effects of microamperage, medium, and bacterial concentration on iontophoretic killing of bacteria in fluid. Antimicrob. Agents Chemother. 33, 442–447. doi: 10.1128/AAC.33.4.442
Decramer, S., Gonzalez de Peredo, A., Breuil, B., Mischak, H., Monsarrat, B., Bascands, J. L., et al. (2008). Urine in clinical proteomics. Mol. Cell. Proteomics 7, 1850–1862. doi: 10.1074/mcp.R800001-MCP200
Deutch, C. E., Arballo, M. E., Cooks, L. N., Gomes, J. M., Williams, T. M., Aboul-Fadl, T., et al. (2006). Susceptibility of Escherichia coli to L-selenaproline and other L-proline analogues in laboratory culture media and normal human urine. Lett. Appl. Microbiol. 43, 392–398. doi: 10.1111/j.1472-765X.2006.01979.x
Dinnbier, U., Limpinsel, E., Schmid, R., and Bakker, E. P. (1988). Transient accumulation of potassium glutamate and its replacement by trehalose during adaptation of growing cells of Escherichia coli K-12 to elevated sodium chloride concentrations. Arch. Microbiol. 150, 348–357. doi: 10.1007/BF00408306
Domergue, R., Castaño, I., De Las Peñas, A., Zupancic, M., Lockatell, V., Hebel, J. R., et al. (2005). Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308, 866–870. doi: 10.1126/science.1108640
Doremus, R. H., Teich, S., and Silvis, P. X. (1978). Crystallization of calcium oxalate from synthetic urine. Invest. Urol. 15, 469–472.
Duell, B. L., Carey, A. J., Tan, C. K., Cui, X., Webb, R. I., Totsika, M., et al. (2012). Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection. J. Immunol. 188, 781–792. doi: 10.4049/jimmunol.1101231
Fischer, H., Lutay, N., Ragnarsdóttir, B., Yadav, M., Jönsson, K., Urbano, A., et al. (2010). Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection. PLoS Pathog. 6:e1001109. doi: 10.1371/journal.ppat.1001109
Frendéus, B., Wachtler, C., Hedlund, M., Fischer, H., Samuelsson, P., Svensson, M., et al. (2001). Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation. Mol. Microbiol. 40, 37–51. doi: 10.1046/j.1365-2958.2001.02361.x
Garcia, E. C., Brumbaugh, A. R., and Mobley, H. L. (2011). Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection. Infect. Immun. 79, 1225–1235. doi: 10.1128/IAI.01222-10
Gardner, G. L., and Doremus, R. H. (1978). Crystal growth inhibitors in human urine. Effect on calcium oxalate kinetics. Invest. Urol. 15, 478–485.
Gonzalez-Chavez, S. A., Arevalo-Gallegos, S., and Rascon-Cruz, Q. (2009). Lactoferrin: structure, function and applications. Int. J. Antimicrob. Agents 33, 301, e301–e308. doi: 10.1016/j.ijantimicag.2008.07.020
Gordon, D. M., and Riley, M. A. (1992). A theoretical and experimental analysis of bacterial growth in the bladder. Mol. Microbiol. 6, 555–562. doi: 10.1111/j.1365-2958.1992.tb01500.x
Grases, F., and Llobera, A. (1998). Experimental model to study sedimentary kidney stones. Micron 29, 105–111. doi: 10.1016/S0968-4328(98)00006-7
Greene, S. E., Hibbing, M. E., Janetka, J., Chen, S. L., and Hultgren, S. J. (2015). Human urine decreases function and expression of Type 1 pili in uropathogenic Escherichia coli. MBio 6:e00820. doi: 10.1128/mBio.00820-15
Griffith, D. P., Musher, D. M., and Itin, C. (1976). Urease. The primary cause of infection-induced urinary stones. Invest. Urol. 13, 346–350.
Grönberg-Hernández, J., Sundén, F., Connolly, J., Svanborg, C., and Wullt, B. (2011). Genetic control of the variable innate immune response to asymptomatic bacteriuria. PLoS ONE 6:e28289. doi: 10.1371/journal.pone.0028289
Guo, K., and Li, L. (2009). Differential 12C-/13C-isotope dansylation labeling and fast liquid chromatography/mass spectrometry for absolute and relative quantification of the metabolome. Anal. Chem. 81, 3919–3932. doi: 10.1021/ac900166a
Gutierrez, C., Ardourel, M., Bremer, E., Middendorf, A., Boos, W., and Ehmann, U. (1989). Analysis and DNA sequence of the osmoregulated treA gene encoding the periplasmic trehalase of Escherichia coli K12. Mol. Gen. Genet. 217, 347–354. doi: 10.1007/BF02464903
Hagan, E. C., and Mobley, H. L. (2009). Haem acquisition is facilitated by a novel receptor Hma and required by uropathogenic Escherichia coli for kidney infection. Mol. Microbiol. 71, 79–91. doi: 10.1111/j.1365-2958.2008.06509.x
Hand, W. L., Smith, J. W., and Sanford, J. P. (1971). The antibacterial effect of normal and infected urinary bladder. J. Lab. Clin. Med. 77, 605–615.
Hannan, T. J., Mysorekar, I. U., Hung, C. S., Isaacson-Schmid, M. L., and Hultgren, S. J. (2010). Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog. 6:e1001042. doi: 10.1371/journal.ppat.1001042
Hannan, T. J., Totsika, M., Mansfield, K. J., Moore, K. H., Schembri, M. A., and Hultgren, S. J. (2012). Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol. Rev. 36, 616–648. doi: 10.1111/j.1574-6976.2012.00339.x
Håversen, L. A., Engberg, I., Baltzer, L., Dolphin, G., Hanson, L. A., and Mattsby-Baltzer, I. (2000). Human lactoferrin and peptides derived from a surface-exposed helical region reduce experimental Escherichia coli urinary tract infection in mice. Infect. Immun. 68, 5816–5823. doi: 10.1128/IAI.68.10.5816-5823.2000
Hood, M. I., and Skaar, E. P. (2012). Nutritional immunity: transition metals at the pathogen-host interface. Nat. Rev. Microbiol. 10, 525–537. doi: 10.1038/nrmicro2836
Hooton, T. M., Scholes, D., Stapleton, A. E., Roberts, P. L., Winter, C., Gupta, K., et al. (2000). A prospective study of asymptomatic bacteriuria in sexually active young women. N. Engl. J. Med. 343, 992–997. doi: 10.1056/NEJM200010053431402
Hryckowian, A. J., Baisa, G. A., Schwartz, K. J., and Welch, R. A. (2015). dsdA does not affect colonization of the murine urinary tract by Escherichia coli CFT073. PLoS ONE 10:e0138121. doi: 10.1371/journal.pone.0138121
Huang, Y., Nishikawa, T., Satoh, K., Iwata, T., Fukushima, T., Santa, T., et al. (1998). Urinary excretion of D-serine in human: comparison of different ages and species. Biol. Pharm. Bull. 21, 156–162. doi: 10.1248/bpb.21.156
Hull, R., Rudy, D., Donovan, W., Svanborg, C., Wieser, I., Stewart, C., et al. (2000). Urinary tract infection prophylaxis using Escherichia coli 83972 in spinal cord injured patients. J. Urol. 163, 872–877. doi: 10.1016/S0022-5347(05)67823-8
Ipe, D. S., Ben Zakour, N. L., Sullivan, M. J., Beatson, S. A., Ulett, K. B., Benjamin, W. H., et al. (2016). Discovery and characterization of human urine utilization by asymptomatic bacteriuria streptococcus agalactiae. Infect. Immun. 84, 307–319. doi: 10.1128/IAI.00938-15
Ipe, D. S., Sundac, L., Benjamin, W. H. Jr., Moore, K. H., and Ulett, G. C. (2013). Asymptomatic bacteriuria: prevalence rates of causal microorganisms, etiology of infection in different patient populations, and recent advances in molecular detection. FEMS Microbiol. Lett. 346, 1–10. doi: 10.1111/1574-6968.12204
Jain, N., Kohli, R., Cook, E., Gialanella, P., Chang, T., and Fries, B. C. (2007). Biofilm formation by and antifungal susceptibility of Candida isolates from urine. Appl. Environ. Microbiol. 73, 1697–1703. doi: 10.1128/AEM.02439-06
Järvisalo, J., Olkinuora, M., Kiilunen, M., Kivistö, H., Ristola, P., Tossavainen, A., et al. (1992). Urinary and blood manganese in occupationally nonexposed populations and in manual metal arc welders of mild steel. Int. Arch. Occup. Environ. Health 63, 495–501. doi: 10.1007/BF00572116
Johnson, J. R., Clabots, C., and Rosen, H. (2006). Effect of inactivation of the global oxidative stress regulator oxyR on the colonization ability of Escherichia coli O1:K1:H7 in a mouse model of ascending urinary tract infection. Infect. Immun. 74, 461–468. doi: 10.1128/IAI.74.1.461-468.2006
King, J. E., Aal Owaif, H. A., Jia, J., and Roberts, I. S. (2015). Phenotypic heterogeneity in expression of the K1 polysaccharide capsule of uropathogenic Escherichia coli and downregulation of the capsule genes during growth in urine. Infect. Immun. 83, 2605–2613. doi: 10.1128/IAI.00188-15
Klemm, P., Hancock, V., and Schembri, M. A. (2007). Mellowing out: adaptation to commensalism by Escherichia coli asymptomatic bacteriuria strain 83972. Infect. Immun. 75, 3688–3695. doi: 10.1128/IAI.01730-06
Klemm, P., Roos, V., Ulett, G. C., Svanborg, C., and Schembri, M. A. (2006). Molecular characterization of the Escherichia coli asymptomatic bacteriuria strain 83972: the taming of a pathogen. Infect. Immun. 74, 781–785. doi: 10.1128/IAI.74.1.781-785.2006
Kline, K. A., Schwartz, D. J., Gilbert, N. M., Hultgren, S. J., and Lewis, A. L. (2012). Immune modulation by group B Streptococcus influences host susceptibility to urinary tract infection by uropathogenic Escherichia coli. Infect. Immun. 80, 4186–4194. doi: 10.1128/IAI.00684-12
Kucheria, R., Dasgupta, P., Sacks, S. H., Khan, M. S., and Sheerin, N. S. (2005). Urinary tract infections: new insights into a common problem. Postgrad. Med. J. 81, 83–86. doi: 10.1136/pgmj.2004.023036
Kunin, C. M., Hua, T. H., and Bakaletz, L. O. (1995). Effect of salicylate on expression of flagella by Escherichia coli and Proteus, Providencia, and Pseudomonas spp. Infect. Immun. 63, 1796–1799.
Kunin, C. M., Hua, T. H., Guerrant, R. L., and Bakaletz, L. O. (1994). Effect of salicylate, bismuth, osmolytes, and tetracycline resistance on expression of fimbriae by Escherichia coli. Infect. Immun. 62, 2178–2186.
Kunin, C. M., Hua, T. H., Van Arsdale White, L., and Villarejo, M. (1992). Growth of Escherichia coli in human urine: role of salt tolerance and accumulation of glycine betaine. J. Infect. Dis. 166, 1311–1315. doi: 10.1093/infdis/166.6.1311
Laimins, L. A., Rhoads, D. B., Altendorf, K., and Epstein, W. (1978). Identification of the structural proteins of an ATP-driven potassium transport system in Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 75, 3216–3219. doi: 10.1073/pnas.75.7.3216
Landete, J. M., García-Haro, L., Blasco, A., Manzanares, P., Berbegal, C., Monedero, V., et al. (2010). Requirement of the Lactobacillus casei MaeKR two-component system for L-malic acid utilization via a malic enzyme pathway. Appl. Environ. Microbiol. 76, 84–95. doi: 10.1128/AEM.02145-09
La Rosa, S. L., Diep, D. B., Nes, I. F., and Brede, D. A. (2012). Construction and application of a luxABCDE reporter system for real-time monitoring of Enterococcus faecalis gene expression and growth. Appl. Environ. Microbiol. 78, 7003–7011. doi: 10.1128/AEM.02018-12
Lee, S. C., Hutchinson, J. M., Inn, K. G., and Thein, M. (1995). An intercomparison study of 237Np determination in artificial urine samples. Health Phys. 68, 350–358. doi: 10.1097/00004032-199503000-00007
Lehman, S. M., and Donlan, R. M. (2015). Bacteriophage-mediated control of a two-species biofilm formed by microorganisms causing catheter-associated urinary tract infections in an in vitro urinary catheter model. Antimicrob. Agents Chemother. 59, 1127–1137. doi: 10.1128/AAC.03786-14
Leonhardt, K. O., and Landes, R. R. (1963). Oxygen tension of the urine and renal structures. Preliminary report of clinical findings. N. Engl. J. Med. 269, 115–121. doi: 10.1056/NEJM196307182690301
Lomberg, H., Hanson, L. A., Jacobsson, B., Jodal, U., Leffler, H., and Edén, C. S. (1983). Correlation of P blood group, vesicoureteral reflux, and bacterial attachment in patients with recurrent pyelonephritis. N. Engl. J. Med. 308, 1189–1192. doi: 10.1056/NEJM198305193082003
Low, Y. L., Jakubovics, N. S., Flatman, J. C., Jenkinson, H. F., and Smith, A. W. (2003). Manganese-dependent regulation of the endocarditis-associated virulence factor EfaA of Enterococcus faecalis. J. Med. Microbiol. 52, 113–119. doi: 10.1099/jmm.0.05039-0
Mabbett, A. N., Ulett, G. C., Watts, R. E., Tree, J. J., Totsika, M., Ong, C. L., et al. (2009). Virulence properties of asymptomatic bacteriuria Escherichia coli. Int. J. Med. Microbiol. 299, 53–63. doi: 10.1016/j.ijmm.2008.06.003
Mansouri, M. D., and Darouiche, R. O. (2008). In-vitro activity and in-vivo efficacy of catheters impregnated with chloroxylenol and thymol against uropathogens. Clin. Microbiol. Infect. 14, 190–192. doi: 10.1111/j.1469-0691.2007.01894.x
Martino, P. D., Fursy, R., Bret, L., Sundararaju, B., and Phillips, R. S. (2003). Indole can act as an extracellular signal to regulate biofilm formation of Escherichia coli and other indole-producing bacteria. Can. J. Microbiol. 49, 443–449. doi: 10.1139/w03-056
Mayrovitz, H. N., and Sims, N. (2001). Biophysical effects of water and synthetic urine on skin. Adv. Skin Wound Care 14, 302–308. doi: 10.1097/00129334-200111000-00013
Meury, J., Robin, A., and Monnier-Champeix, P. (1985). Turgor-controlled K+ fluxes and their pathways in Escherichia coli. Eur. J. Biochem. 151, 613–619. doi: 10.1111/j.1432-1033.1985.tb09148.x
Miller, J. D., Randolph, A. D., and Drach, G. W. (1977). Observations upon calcium oxalate crystallization kinetics in simulated urine. J. Urol. 117, 342–345.
Minuth, J. N., Musher, D. M., and Thorsteinsson, S. B. (1976). Inhibition of the antibacterial activity of gentamicin by urine. J. Infect. Dis. 133, 14–21. doi: 10.1093/infdis/133.1.14
Negri, M., Silva, S., Breda, D., Henriques, M., Azeredo, J., and Oliveira, R. (2012). Candida tropicalis biofilms: effect on urinary epithelial cells. Microb. Pathog. 53, 95–99. doi: 10.1016/j.micpath.2012.05.006
Negri, M., Silva, S., Capoci, I. R., Azeredo, J., and Henriques, M. (2015). Candida tropicalis biofilms: biomass, metabolic activity and secreted aspartyl proteinase production. Mycopathologia. doi: 10.1007/s11046-015-9964-4. [Epub ahead of print].
Negri, M., Silva, S., Henriques, M., Azeredo, J., Svidzinski, T., and Oliveira, R. (2011). Candida tropicalis biofilms: artificial urine, urinary catheters and flow model. Medical Mycology 49, 739–747. doi: 10.3109/13693786.2011.560619
Nickel, J. C., Ruseska, I., Wright, J. B., and Costerton, J. W. (1985). Tobramycin resistance of Pseudomonas aeruginosa cells growing as a biofilm on urinary catheter material. Antimicrob. Agents Chemother. 27, 619–624. doi: 10.1128/AAC.27.4.619
Nicolle, L. E. (1997). Asymptomatic bacteriuria in the elderly. Infect. Dis. Clin. North Am. 11, 647–662. doi: 10.1016/S0891-5520(05)70378-0
Nicolle, L. E. (1999). Urinary infections in the elderly: symptomatic of asymptomatic? Int. J. Antimicrob. Agents 11, 265–268.
Nicolle, L. E. (2014). Asymptomatic bacteriuria. Curr. Opin. Infect. Dis. 27, 90–96. doi: 10.1097/QCO.0000000000000019
Nicolle, L. E., Bradley, S., Colgan, R., Rice, J. C., Schaeffer, A., and Hooton, T. M. (2005). Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin. Infect. Dis. 40, 643–654. doi: 10.1086/427507
Nielubowicz, G. R., and Mobley, H. L. (2010). Host-pathogen interactions in urinary tract infection. Nat. Rev. Urol. 7, 430–441. doi: 10.1038/nrurol.2010.101
O'grady, F., and Cattell, W. R. (1966a). Kinetics of urinary tract infection. I. Upper urinary tract. Br. J. Urol. 38, 149–155.
O'grady, F., and Cattell, W. R. (1966b). Kinetics of urinary tract infection. II. The bladder. Br. J. Urol. 38, 156–162.
O'grady, F., and Pennington, J. H. (1966). Bacterial growth in an in vitro system simulating conditions in the urinary bladder. Br. J. Exp. Pathol. 47, 152–157.
Ong, C. L., Beatson, S. A., McEwan, A. G., and Schembri, M. A. (2009). Conjugative plasmid transfer and adhesion dynamics in an Escherichia coli biofilm. Appl. Environ. Microbiol. 75, 6783–6791. doi: 10.1128/AEM.00974-09
Ong, C. L., Beatson, S. A., Totsika, M., Forestier, C., McEwan, A. G., and Schembri, M. A. (2010). Molecular analysis of type 3 fimbrial genes from Escherichia coli, Klebsiella and Citrobacter species. BMC Microbiol. 10:183. doi: 10.1186/1471-2180-10-183
Opalko, F. J., Adair, J. H., and Khan, S. R. (1997). Heterogeneous nucleation of calcium oxalate trihydrate in artificial urine by constant composition. J. Cryst. Growth 181, 410–417. doi: 10.1016/S0022-0248(97)00222-4
Pätzold, R., Schieber, A., and Brückner, H. (2005). Gas chromatographic quantification of free D-amino acids in higher vertebrates. Biomed. Chromatogr. 19, 466–473. doi: 10.1002/bmc.515
Phuengkham, H., and Nasongkla, N. (2015). Development of antibacterial coating on silicone surface via chlorhexidine-loaded nanospheres. J. Mater. Sci. Mater. Med. 26:78. doi: 10.1007/s10856-015-5418-2
Putnam, D. F., Company-West, M. D. A., Center, L. R., Aeronautics, U. S. N., and Administration, S. (1971). Composition and Concentrative Properties of Human Urine. Washington, DC: National Aeronautics and Space Administration.
Raffi, H. S., Bates, J. M. Jr., Laszik, Z., and Kumar, S. (2005). Tamm-Horsfall protein acts as a general host-defense factor against bacterial cystitis. Am. J. Nephrol. 25, 570–578. doi: 10.1159/000088990
Ragnarsdóttir, B., and Svanborg, C. (2012). Susceptibility to acute pyelonephritis or asymptomatic bacteriuria: host-pathogen interaction in urinary tract infections. Pediatric Nephrol. 27, 2017–2029. doi: 10.1007/s00467-011-2089-1
Rane, H. S., Bernardo, S. M., Howell, A. B., and Lee, S. A. (2014). Cranberry-derived proanthocyanidins prevent formation of Candida albicans biofilms in artificial urine through biofilm- and adherence-specific mechanisms. J. Antimicrob. Chemother. 69, 428–436. doi: 10.1093/jac/dkt398
Robertson, W. G., Peacock, M., and Nordin, B. E. (1968). Activity products in stone-forming and non-stone-forming urine. Clin. Sci. 34, 579–594.
Robertson, W. G., and Scurr, D. S. (1986). Modifiers of calcium oxalate crystallization found in urine. I. Studies with a continuous crystallizer using an artificial urine. J. Urol. 135, 1322–1326.
Robertson, W. G., Scurr, D. S., and Bridge, C. M. (1981). Factors influencing the crystallization of calcium-oxalate in urine - critique. J. Cryst. Growth 53, 182–194. doi: 10.1016/0022-0248(81)90064-6
Robinson, A. V., Fisher, D. R., and Hadley, R. T. (1984). Technical Evaluation of Draft ANSI Standard N13.30, Performance Criteria for Radioassay. Richland, WA: Pacific Northwest Laboratory.
Rodgers, A. L., and Wandt, M. A. (1991). Influence of ageing, pH and various additives on crystal formation in artificial urine. Scanning Microsc. 5, 697–705. discussion: 705–696.
Roesch, P. L., Redford, P., Batchelet, S., Moritz, R. L., Pellett, S., Haugen, B. J., et al. (2003). Uropathogenic Escherichia coli use D-serine deaminase to modulate infection of the murine urinary tract. Mol. Microbiol. 49, 54–67. doi: 10.1046/j.1365-2958.2003.03543.x
Ronald, A., and Ludwig, E. (2001). Urinary tract infections in adults with diabetes. Int. J. Antimicrob. Agents 17, 287–292. doi: 10.1016/S0924-8579(00)00356-3
Roos, V., Nielsen, E. M., and Klemm, P. (2006a). Asymptomatic bacteriuria Escherichia coli strains: adhesins, growth and competition. FEMS Microbiol. Lett. 262, 22–30. doi: 10.1111/j.1574-6968.2006.00355.x
Roos, V., Ulett, G. C., Schembri, M. A., and Klemm, P. (2006b). The asymptomatic bacteriuria Escherichia coli strain 83972 outcompetes uropathogenic E. coli strains in human urine. Infect. Immun. 74, 615–624. doi: 10.1128/IAI.74.1.615-624.2006
Rose, M. B. (1975). Renal stone formation. The inhibitory effect of urine on calcium oxalate precipitation. Invest. Urol. 12, 428–433.
Rubin, R. H., Shapiro, E. D., Andriole, V. T., Davis, R. J., and Stamm, W. E. (1992). Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin. Infect. Dis. 15(Suppl. 1), S216–S227. doi: 10.1093/clind/15.supplement_1.s216
Rudick, C. N., Billips, B. K., Pavlov, V. I., Yaggie, R. E., Schaeffer, A. J., and Klumpp, D. J. (2010). Host-pathogen interactions mediating pain of urinary tract infection. J. Infect. Dis. 201, 1240–1249. doi: 10.1086/651275
Russo, T. A., Jodush, S. T., Brown, J. J., and Johnson, J. R. (1996). Identification of two previously unrecognized genes (guaA and argC) important for uropathogenesis. Mol. Microbiol. 22, 217–229. doi: 10.1046/j.1365-2958.1996.00096.x
Russo, T. A., Olson, R., Macdonald, U., Beanan, J., and Davidson, B. A. (2015). Aerobactin, but not yersiniabactin, salmochelin, or enterobactin, enables the growth/survival of hypervirulent (hypermucoviscous) Klebsiella pneumoniae ex vivo and in vivo. Infect. Immun. 83, 3325–3333. doi: 10.1128/IAI.00430-15
Ryall, R. L., Harnett, R. M., Hibberd, C. M., Mazzachi, B. C., Mazzachi, R. D., and Marshall, V. R. (1987). Urinary risk factors in calcium oxalate stone disease: comparison of men and women. Br. J. Urol. 60, 480–488. doi: 10.1111/j.1464-410X.1987.tb05025.x
Säemann, M. D., Weichhart, T., Hörl, W. H., and Zlabinger, G. J. (2005). Tamm-Horsfall protein: a multilayered defence molecule against urinary tract infection. Eur. J. Clin. Invest. 35, 227–235. doi: 10.1111/j.1365-2362.2005.01483.x
Sakinç, T., Michalski, N., Kleine, B., and Gatermann, S. G. (2009). The uropathogenic species Staphylococcus saprophyticus tolerates a high concentration of D-serine. FEMS Microbiol. Lett. 299, 60–64. doi: 10.1111/j.1574-6968.2009.01731.x
Sako, S., Kariyama, R., Mitsuhata, R., Yamamoto, M., Wada, K., Ishii, A., et al. (2014). Molecular epidemiology and clinical implications of metallo-beta-lactamase-producing Pseudomonas aeruginosa isolated from urine. Acta Med. Okayama 68, 89–99.
Salvador, E., Wagenlehner, F., Kohler, C. D., Mellmann, A., Hacker, J., Svanborg, C., et al. (2012). Comparison of asymptomatic bacteriuria Escherichia coli isolates from healthy individuals versus those from hospital patients shows that long-term bladder colonization selects for attenuated virulence phenotypes. Infect. Immun. 80, 668–678. doi: 10.1128/IAI.06191-11
Samaranayake, Y. H., Bandara, H. M., Cheung, B. P., Yau, J. Y., Yeung, S. K., and Samaranayake, L. P. (2014). Enteric Gram-negative bacilli suppress Candida biofilms on Foley urinary catheters. APMIS 122, 47–58. doi: 10.1111/apm.12098
Sarada, B., and Satyanarayana, U. (1991). Urinary composition in men and women and the risk of urolithiasis. Clin. Biochem. 24, 487–490. doi: 10.1016/S0009-9120(05)80007-4
Schneeberger, C., Geerlings, S. E., Middleton, P., and Crowther, C. A. (2012). Interventions for preventing recurrent urinary tract infection during pregnancy. Cochrane Database Syst. Rev. 11:CD009279. doi: 10.1002/14651858.CD009279.pub2
Schneeberger, C., Kazemier, B. M., and Geerlings, S. E. (2014). Asymptomatic bacteriuria and urinary tract infections in special patient groups: women with diabetes mellitus and pregnant women. Curr. Opin. Infect. Dis. 27, 108–114. doi: 10.1097/QCO.0000000000000028
Shaykhutdinov, R. A., Macinnis, G. D., Dowlatabadi, R., Weljie, A. M., and Vogel, H. J. (2009). Quantitative analysis of metabolite concentrations in human urine samples using 13C{1H} NMR spectroscopy. Metabolomics 5, 307–317. doi: 10.1007/s11306-009-0155-5
Sheewin, N. S. (2011). Urinary tract infection. Medicine 39, 384–389. doi: 10.1016/j.mpmed.2011.04.003
Shepard, B. D., and Gilmore, M. S. (2002). Differential expression of virulence-related genes in Enterococcus faecalis in response to biological cues in serum and urine. Infect. Immun. 70, 4344–4352. doi: 10.1128/IAI.70.8.4344-4352.2002
Shields-Cutler, R. R., Crowley, J. R., Hung, C. S., Stapleton, A. E., Aldrich, C. C., Marschall, J., et al. (2015). Human urinary composition controls antibacterial activity of siderocalin. J. Biol. Chem. 290, 15949–15960. doi: 10.1074/jbc.M115.645812
Silva, S., Negri, M., Henriques, M., Oliveira, R., Williams, D., and Azeredo, J. (2010). Silicone colonization by non-Candida albicans Candida species in the presence of urine. J. Med. Microbiol. 59, 747–754. doi: 10.1099/jmm.0.017517-0
Snyder, J. A., Haugen, B. J., Buckles, E. L., Lockatell, C. V., Johnson, D. E., Donnenberg, M. S., et al. (2004). Transcriptome of uropathogenic Escherichia coli during urinary tract infection. Infect. Immun. 72, 6373–6381. doi: 10.1128/IAI.72.11.6373-6381.2004
Sobel, J. D. (1985). New aspects of pathogenesis of lower urinary tract infections. Urology 26, 11–16.
Soler-García, A. A., Johnson, D., Hathout, Y., and Ray, P. E. (2009). Iron-related proteins: candidate urine biomarkers in childhood HIV-associated renal diseases. Clin. J. Am. Soc. Nephrol. 4, 763–771. doi: 10.2215/CJN.0200608
Stamey, T. A., and Mihara, G. (1980). Observations on the growth of urethral and vaginal bacteria in sterile urine. J. Urol. 124, 461–463.
Storer, M. K., Hibbard-Melles, K., Davis, B., and Scotter, J. (2011). Detection of volatile compounds produced by microbial growth in urine by selected ion flow tube mass spectrometry (SIFT-MS). J. Microbiol. Methods 87, 111–113. doi: 10.1016/j.mimet.2011.06.012
Strøm, A. R., and Kaasen, I. (1993). Trehalose metabolism in Escherichia coli: stress protection and stress regulation of gene expression. Mol. Microbiol. 8, 205–210. doi: 10.1111/j.1365-2958.1993.tb01564.x
Styrvold, O. B., and Strøm, A. R. (1991). Synthesis, accumulation, and excretion of trehalose in osmotically stressed Escherichia coli K-12 strains: influence of amber suppressors and function of the periplasmic trehalase. J. Bacteriol. 173, 1187–1192.
Sundén, F., Håkansson, L., Ljunggren, E., and Wullt, B. (2006). Bacterial interference–is deliberate colonization with Escherichia coli 83972 an alternative treatment for patients with recurrent urinary tract infection? Int. J. Antimicrob. Agents 28(Suppl. 1), S26–S29. doi: 10.1016/j.ijantimicag.2006.05.007
Svanborg, C., Bergsten, G., Fischer, H., Godaly, G., Gustafsson, M., Karpman, D., et al. (2006). Uropathogenic Escherichia coli as a model of host-parasite interaction. Curr. Opin. Microbiol. 9, 33–39. doi: 10.1016/j.mib.2005.12.012
Tan, C. K., Carey, A. J., Cui, X., Webb, R. I., Ipe, D., Crowley, M., et al. (2012). Genome-wide mapping of cystitis due to Streptococcus agalactiae and Escherichia coli in mice identifies a unique bladder transcriptome that signifies pathogen-specific antimicrobial defense against urinary tract infection. Infect. Immun. 80, 3145–3160. doi: 10.1128/IAI.00023-12
Tasevska, N., Runswick, S. A., McTaggart, A., and Bingham, S. A. (2005). Urinary sucrose and fructose as biomarkers for sugar consumption. Cancer Epidemiol. Biomarkers Prevent. 14, 1287–1294. doi: 10.1158/1055-9965.EPI-04-0827
Tielen, P., Rosin, N., Meyer, A. K., Dohnt, K., Haddad, I., Jänsch, L., et al. (2013). Regulatory and metabolic networks for the adaptation of Pseudomonas aeruginosa biofilms to urinary tract-like conditions. PLoS ONE 8:e71845. doi: 10.1371/journal.pone.0071845
Torffvit, O., and Agardh, C. D. (1993). Tubular secretion of Tamm-Horsfall protein is decreased in type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Nephron 65, 227–231. doi: 10.1159/000187479
Torzewska, A., Budzynska, A., Bialczak-Kokot, M., and Rózalski, A. (2014). In vitro studies of epithelium-associated crystallization caused by uropathogens during urinary calculi development. Microb. Pathog. 71–72, 25–31. doi: 10.1016/j.micpath.2014.04.007
Torzewska, A., and Rózalski, A. (2014). In vitro studies on the role of glycosaminoglycans in crystallization intensity during infectious urinary stones formation. APMIS 122, 505–511. doi: 10.1111/apm.12191
Torzewska, A., and Rózalski, A. (2015). Various intensity of Proteus mirabilis-induced crystallization resulting from the changes in the mineral composition of urine. Acta Biochim. Pol. 62, 127–132. doi: 10.18388/abp.2014_882
Torzewska, A., Staczek, P., and Rózalski, A. (2003). Crystallization of urine mineral components may depend on the chemical nature of Proteus endotoxin polysaccharides. J. Med. Microbiol. 52, 471–477. doi: 10.1099/jmm.0.05161-0
Ulett, G. C., Totsika, M., Schaale, K., Carey, A. J., Sweet, M. J., and Schembri, M. A. (2013). Uropathogenic Escherichia coli virulence and innate immune responses during urinary tract infection. Curr. Opin. Microbiol. 16, 100–107. doi: 10.1016/j.mib.2013.01.005
Uppuluri, P., Dinakaran, H., Thomas, D. P., Chaturvedi, A. K., and Lopez-Ribot, J. L. (2009). Characteristics of Candida albicans biofilms grown in a synthetic urine medium. J. Clin. Microbiol. 47, 4078–4083. doi: 10.1128/JCM.01377-09
Vebø, H. C., Solheim, M., Snipen, L., Nes, I. F., and Brede, D. A. (2010). Comparative genomic analysis of pathogenic and probiotic Enterococcus faecalis isolates, and their transcriptional responses to growth in human urine. PLoS ONE 5:e12489. doi: 10.1371/journal.pone.0012489
Vejborg, R. M., de Evgrafov, M. R., Phan, M. D., Totsika, M., Schembri, M. A., and Hancock, V. (2012). Identification of genes important for growth of asymptomatic bacteriuria Escherichia coli in urine. Infect. Immun. 80, 3179–3188. doi: 10.1128/IAI.00473-12
Watts, R. E., Hancock, V., Ong, C. L., Vejborg, R. M., Mabbett, A. N., Totsika, M., et al. (2010). Escherichia coli isolates causing asymptomatic bacteriuria in catheterized and noncatheterized individuals possess similar virulence properties. J. Clin. Microbiol. 48, 2449–2458. doi: 10.1128/JCM.01611-09
Watts, R. E., Tan, C. K., Ulett, G. C., Carey, A. J., Totsika, M., Idris, A., et al. (2012a). Escherichia coli 83972 expressing a P fimbriae oligosaccharide receptor mimic impairs adhesion of uropathogenic E. coli. J. Infect. Dis. 206, 1242–1249. doi: 10.1093/infdis/jis493
Watts, R. E., Totsika, M., Challinor, V. L., Mabbett, A. N., Ulett, G. C., De Voss, J. J., et al. (2012b). Contribution of siderophore systems to growth and urinary tract colonization of asymptomatic bacteriuria Escherichia coli. Infect. Immun. 80, 333–344. doi: 10.1128/IAI.05594-11
Wenzler-Röttele, S., Dettenkofer, M., Schmidt-Eisenlohr, E., Gregersen, A., Schulte-Monting, J., and Tvede, M. (2006). Comparison in a laboratory model between the performance of a urinary closed system bag with double non-return valve and that of a single valve system. Infection 34, 214–218. doi: 10.1007/s15010-006-5626-2
Wernli, L., Bonkat, G., Gasser, T. C., Bachmann, A., and Braissant, O. (2013). Use of isothermal microcalorimetry to quantify the influence of glucose and antifungals on the growth of Candida albicans in urine. J. Appl. Microbiol. 115, 1186–1193. doi: 10.1111/jam.12306
Wilks, S. A., Fader, M. J., and Keevil, C. W. (2015). Novel insights into the Proteus mirabilis crystalline biofilm using real-time imaging. PLoS ONE 10:e0141711. doi: 10.1371/journal.pone.0141711
Wishart, D. S., Knox, C., Guo, A. C., Eisner, R., Young, N., Gautam, B., et al. (2009). HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 37, D603–D610. doi: 10.1093/nar/gkn810
Wullt, B. (2003). The role of P fimbriae for Escherichia coli establishment and mucosal inflammation in the human urinary tract. Int. J. Antimicrob. Agents 21, 605–621. doi: 10.1016/S0924-8579(02)00328-X
Wullt, B., Connell, H., Röllano, P., Månsson, W., Colleen, S., and Svanborg, C. (1998). Urodynamic factors influence the duration of Escherichia coli bacteriuria in deliberately colonized cases. J. Urol. 159, 2057–2062. doi: 10.1016/S0022-5347(01)63246-4
Keywords: bacteriuria, asymptomatic bacteriuria, urinary tract infection, urine, urinalysis, uropathogen, synthetic human urine, artificial urine
Citation: Ipe DS, Horton E and Ulett GC (2016) The Basics of Bacteriuria: Strategies of Microbes for Persistence in Urine. Front. Cell. Infect. Microbiol. 6:14. doi: 10.3389/fcimb.2016.00014
Received: 10 November 2015; Accepted: 22 January 2016;
Published: 08 February 2016.
Edited by:
Matthew S. Francis, Umeå University, SwedenReviewed by:
Charles Martin Dozois, Institut National de la Recherche Scientifique, CanadaUlrich Dobrindt, University of Münster, Germany
Copyright © 2016 Ipe, Horton and Ulett. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Glen C. Ulett, [email protected]