Cover: Urogenital Infections and Inflammations

Urogenital Infections and Inflammations

T.E. Bjerklund Johansen, F. M.E. Wagenlehner, Y.-H. Cho, T. Matsumoto, J. N. Krieger, D. Shoskes, K. Naber

Sex and other host factors influencing urinary tract infection pathogenesis

Patrick D. Olson 1
 David Hunstad 2

1 Medical Scientist Training Program, Washington University School of Medicine, St. Louis, USA
2 Pediatrics / Molecular Microbiology, Washington University School of Medicine, St. Louis, United States


Biological sex represents the most important host factor that influences urinary tract infections (UTIs), which are most commonly caused by uropathogenic Escherichia coli (UPEC). UTI susceptibility varies by sex and age throughout the patient lifespan, although the disease disproportionally afflicts women throughout the middle ages. Substantial male patient populations are also affected, and morbidity in complicated UTI is higher in men. This review highlights sex-related discrepancies in the disease, and how sex may influence the pathogenesis, outcomes, and treatment of ascending UTI.

1 Introduction

“From womb to tomb” it matters, argues the 2001 Institute of Medicine report [1]; biological sex should be a fundamental consideration in human health and disease. Indeed, a number of human diseases manifest profound sex-based differences in prevalence, incidence, severity, and response to treatment. Yet, sex as a biological variable has long been ignored experimentally in the biomedical sciences and clinically in the application of evidence-based medicine [2], [3]. Research and medicine in the US and other countries are currently on the verge of a paradigm shift in which sex should and will increasingly be considered from bench to bedside [2], [3], [4].

Such a sex bias is well entrenched in our understanding of urinary tract infections (UTIs), a collection of diseases which have been both prejudiced and understudied because of their disproportionate affliction of women and long-standing experimental and clinical sex biases. UTIs are among the most common bacterial infections that plague humans. On an epidemiologic basis, community-onset UTI is widely viewed as a disease only of women; indeed, its occurrence between 2 and 60 years of age is almost exclusive to females, and it is estimated that at least half of American women will suffer a UTI during their lifetimes [5]. However, in certain populations the incidence of male UTI matches or exceeds that in females; epidemiologic data also suggest a sex difference in morbidity from upper-tract UTI [6], [7], [8], [9]. To better understand resistance and susceptibility mechanisms to UTI, it is important that we consider age- and sex-related discrepancies that are evident in the disease, and how sex and other host factors may influence the pathogenesis and outcomes of ascending UTI.

2 Host factors influencing UTI

Though contemporary and emerging technologies will enable further investigation of the presumed sterility of the urinary tract, microbiologic health of the urinary tract depends on multiple host factors, including a finely tuned innate inflammatory response, which act to eliminate potential uropathogens from the bladder and kidneys [10], [11], [12], [13]. Despite repetitive exposure of this potentially hospitable, nutrient-rich environment to bacterial pathogens (e.g., following sexual intercourse [14]), bacteriuria in the otherwise healthy human host usually is transient [15], [16], [17]. Host traits that compromise the defenses of the urinary tract augment disease susceptibility, severity, and progression. Forward flow of urine provides a formidable mechanical defense; dysfunctional voiding and other urodynamic abnormalities are clearly associated with increased susceptibility to UTI in children and adults [18]. Such conditions in the adult female likely include pregnancy, which also predisposes to UTI [19]. Factors which increase the hospitability of the bladder microenvironment to infection, such as glycosuria associated with diabetes mellitus, likewise increase susceptibility to UTI [20]; hyperglycemia may also additionally compromise the activity of phagocytes. Finally, impairment of the innate immune response either by immunosuppression or genetic defects in innate components lead to increased frequency of UTI [12]. Multiple efforts to define human genetic variation imparting susceptibility to UTI have been modestly successful. Attention in this realm has been focused largely on host innate immune genes. However, it has also become clear that susceptibility is both polygenic and environmental, and that genetic determinants of distinct clinical syndromes (asymptomatic bacteriuria, cystitis, and pyelonephritis) must be pursued independently.

3 Sex and UTI

However, the host trait that is most influential in the development of UTI is undeniably biological sex. The frequency of UTI changes drastically across the lifespan and varies by sex [21]. As mentioned previously, the occurrence of UTI in middle age is almost exclusive to females. However, certain populations show an increased risk of male UTI.

UTI in young children is common [22], [23]. The sex ratio in UTI incidence among infants is approximately 2:1 – still favoring females, but at a much lower ratio than in later childhood and beyond. In fact, many studies have shown that male UTI cases outnumber females within the first 3–6 months after birth [24], [25], [26], [27], [28], [29], [30], [31]. Thereafter, UTI susceptibility wanes in males throughout later infancy. Infants and young children thus may represent a unique patient population in which to investigate sex differences in UTI. Clinically, prompt diagnosis and treatment of UTI in infancy is necessary to prevent renal scarring and potential long-term complications [32]. Interestingly, a history of maternal UTI during pregnancy has been associated with up to a 5.9-fold higher risk of UTI in both sexes during infancy [33], [34]. It is unclear if this risk arises from inheritance of genetic predisposition to UTI, intrapartum or postpartum transmission of virulent uropathogens from the maternal genitourinary tract to the microbiota of the infant, or other environmental factors.

Though women represent >90% of UTI patients between early childhood and late middle age [5], [35], [36], complicated UTI manifests in both sexes across this time frame in patients with indwelling urinary catheters, diabetes mellitus, spinal cord injuries, immunosuppression, and structural or urodynamic abnormalities. Notably, while female cases of complicated and upper-tract UTI (pyelonephritis) outnumber male cases overall, men carry an increased risk of mortality from these infections [6], [7], [8], [9]. Thousands of men, particularly those of advancing age, also suffer from acute and chronic bacterial prostatitis, a clinical diagnosis with signs, symptoms, and etiological pathogen profiles that overlap substantially with those of lower UTI in females [37], [38]. The incidence of UTI in males increases substantially after 60 years of age, largely because of abnormal voiding patterns due to acquired urodynamic abnormalities (e.g., benign prostatic hyperplasia) [5], [21], [39]. In total, UTIs comprise debilitating diseases with substantial morbidity and occasional mortality among males [37], [38].

Though a number of distinct bacterial pathogens may cause UTI and prostatitis, uropathogenic Escherichia coli (UPEC) predominate among etiological agents in both sexes, causing >80% of community-onset UTI, roughly one fourth of hospital-acquired UTI, and >70% of infectious prostatitis [5], [21], [40]. Our knowledge of the molecular details of UPEC pathogenesis has been developed largely in an exclusively female murine model. In this widely used model of bacterial cystitis, female mice are briefly catheterized and uropathogenic bacteria inoculated into the bladder lumen; however, the bladders of male mice are not reliably accessed by catheter, precluding studies of male cystitis and pyelonephritis using this method. Upon delivery to the female bladder, UPEC and other uropathogens first encounter the stratified transitional epithelium, lined by a single layer of large, multinucleated superficial facet cells apically coated with an array of integral membrane proteins known as uroplakins [41]. UPEC exploit mannose moieties decorating these uroplakins as the receptor for their major virulence determinant, adhesive type 1 pili [42], [43]. Following type 1 pilus-mediated attachment to the uroepithelium, UPEC are rapidly internalized into superficial facet cells [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61]. After a single bacterium has invaded a facet cell, it may then rapidly replicate in the host cell cytoplasm, initially forming loose collections that subsequently coalesce into densely packed intracellular bacterial communities (IBCs) [50]. Infected bladder epithelial cells may be exfoliated, eliminating some IBCs in the urine [62], [63]; meanwhile, a subset of UPEC may flux from the mature IBC, assume a filamentous morphology that resists neutrophil phagocytosis, and initiate further rounds of IBC formation by invading nearby naive epithelial cells [64], [65]. Murine and in vitro evidence for this IBC cascade has been corroborated by detection of shed IBCs in female human urines [66], [67], suggesting that the murine IBC pathway recapitulates acute cystitis in women.

This paradigm, in which cystitis pathogenesis depends on an intracellular cascade, has been recently expanded to male hosts. The technical barriers to modeling UTI in male mice have long been simply accepted in the field, with the rationalization that females comprise the important population of UTI patients anyway. To overcome the technical hurdles, we recently devised and optimized a strategy to induce UTI via mini-surgical inoculation of the bladder in both sexes of mice. Acute UPEC cystitis in male mice recapitulated the intracellular bacterial community pathway previously shown in females [68]. Intracellular bacteria have also been recently identified within exfoliated bladder epithelial cells from the urine of infected male infants [69]; these findings collectively suggest that the IBC cascade is important for the development of acute bacterial cystitis in both sexes.

The sex discrepancies seen in UTI epidemiology have been traditionally attributed to anatomic (and less conclusively, hygienic) factors, including the permissiveness of the surrounding vaginal and perineal environments to microbial colonization, a shorter distance from the anus to the urethral meatus, and shorter urethral length in females. Our data demonstrating similar bladder infectivity between male and female mice after direct inoculation [68] offers empirical data to support this long-standing hypothesis that UTI risk in females is potentiated by these anatomic features, and is not driven by intrinsic epithelial receptivity or comparatively diminished immune resistance within the urinary tract of women. Conversely, normal anatomy represents a key defense against ascending bacterial infection in boys (past infancy) and men [68].

4 Male UTI

Unfortunately, the epidemiology, diagnosis, and treatment of UTI in male populations have been poorly described compared to the robustly studied female populations, although substantial differences exist between them [70]. Infections of male accessory organs, including prostatitis, epididymitis, orchitis, and seminal vesiculitis, can also be classified as exclusively male forms of UTI. UTI in adult male patients is often viewed as “complicated,” if only because of the relative paucity of cases in men compared to women.

Males also exhibit an increase in some specific risk factors that potentiate UTI. A lack of circumcision increases risk for UTI in both infants [71], [72], [73] and adult men [74]. Men have a striking predilection for spinal cord injury, outnumbering female cases four to one; chronic, recurrent UTIs present a difficult and often lifelong challenge in patients with neurogenic bladder arising from such injuries and other causes [75]. Complicated UTI also manifests in hospitalized males with indwelling urinary catheters, those receiving immunosuppression, and those with structural abnormalities (particularly in infancy).

Optimal treatment regimens (antibiotic choice and duration) for uncomplicated UTI in females have been the subject of numerous clinical trials, and the contemporary clinician can rely on published guidelines for these patients [76], while evidence supporting proper choice of antimicrobial agents and duration of therapy for men is less clear. Many expert recommendations call for extended (14 days or longer) courses of antibiotic therapy to treat male UTI [39], [77], [78], [79]. However, a recent study found no differences in acute resolution or recurrence rate between male UTI patients treated for <7 days versus those treated for >7 days; moreover, longer-duration therapy was associated with the subsequent development of Clostridium difficile infection [80]. Ongoing studies and clinical trials are expected to inform the development of more evidence-based and specific recommendations for treating male UTI [81].

5 Hormones

Developing evidence suggests that hormonal milieu, specifically estrogen and testosterone influence, may impact UTI susceptibility and severity. Our increasing knowledge of this field is particularly interesting as it may ultimately inform approaches that represent alternatives to antibiotic treatment.

There are extensive but somewhat conflicting data on the influence of estrogen on susceptibility to UTI. Young adult women, who exhibit the highest estrogen levels, account for the majority of community-onset UTI cases, and high estrogen levels have been linked to increased UTI susceptibility [82]. However, post-menopausal females also experience an increased incidence of UTI, which in some cases has been treated with estrogen supplementation. Results from murine studies employing ovariectomized and/or estrogen-supplemented females to examine the influences of estradiol on UTI pathogenesis are likewise conflicting. Some studies have found modest increases in bladder bacterial burdens in estrogen-depleted hosts, particularly during the acute phase of cystitis [83], [84]. Conversely, we found no change in susceptibility to chronic cystitis or pyelonephritis in ovariectomized female mice [68], and Curran et al. noted an increased risk of upper-tract UTI in mice following estrogen treatment [85]. These experimental models notably bypass the vaginal and periurethral microenvironment, as mice are inoculated by transurethral catheterization of the bladder. Collectively, the available data suggest that the impact of estrogen on bacterial pathogenesis within the urinary tract proper is likely minor. However, many have posited that estrogens may influence periurethral colonization by uropathogens and alter UTI-relevant facets of the vaginal environment (e.g., composition of the vaginal microbiome, dryness, sexual intercourse frequency). In line with this hypothesis, a Cochrane review concluded that topical estrogens show possible benefit in reducing UTI risk, albeit with a number of side effects [86]. Of note, recent evidence suggests that high estradiol levels may cause opposing changes in both bladder fortification and receptivity to infection, providing a viable hypothesis for inconsistent estrogenic influences on UTI. High estradiol levels may induce expression of major adhesive receptors for uropathogens in bladder epithelial cells in vitro (thereby promoting increased bacterial adherence and invasion), while a protective effect may be attributable to its ability to induce antimicrobial peptides during acute UTI [84].

The influence of testosterone on UTI susceptibility has only recently been explored. As described above, our initial investigation of sex differences in murine UTI pathogenesis revealed that susceptibility to acute cystitis remained fairly similar between sexes [68]. However, male mice displayed strikingly higher susceptibility to chronic cystitis and severe pyelonephritis, as well as formation of renal abscess – an event that is very uncommon in immunocompetent female mice [68], [87], [88]. Castration substantially abrogated male susceptibility to UTI, while provision of exogenous testosterone restored severe UTI outcomes, demonstrating a previously unrecognized role of androgens in UTI susceptibility [68]. If testosterone administration also promotes these complicated UTI outcomes in female mice, then modulation of androgens might ultimately be a viable adjunct therapy in some UTI patients. Future investigation using our model of surgical infection for sex comparisons will continue to give insight into mechanistic differences in UTI initiation, progression, and persistence in both male and female hosts [68].

6 Conclusion

Men and women display fundamental differences in their susceptibility to infectious diseases. These dissimilarities stem from a multitude of differences: in pathogen exposure, cultural and behavioral issues, anatomy, hormonal expression, treatment efficacy, socio-economic influences, and many more. Most notably, sex differences in immunity have been clearly described, with females displaying enhanced resistance to many infections because of more robust immune responses controlling pathogens [89], [90], [91]. This enhanced defense in women has been hypothesized to have evolved from the need to protect their fetuses from infection [92], and is associated with the greater frequency and severity in women of many chronic inflammatory and autoimmune diseases [93], [94].

Ascending UTI represents a contradiction to this paradigm, being one of the few infectious diseases which disproportionately afflicts females over males. In considering how biological sex influences UTI, the chief protective mechanism for males is anatomy, while repeated introduction of bacterial pathogens to the urinary tract in females necessitates a finely tuned innate surveillance and defense system as primary protection. Accordingly, traits or interventions which bypass or hamper these defenses represent risk factors for chronic and/or recurrent UTI [13]. As described above, new experimental models that bypass lower anatomic barriers will enable the study of immunologic and other sex differences in cystitis and pyelonephritis. Recent calls by the US National Institutes of Health [4] and in the basic and clinical literature [2], [95], [96] for sex-based research approaches to infectious and other diseases, including a specific focus on UTI [80], [97], should help to accelerate research progress in this arena. Continued work on studying sex differences in these conditions promises to inform the development of novel therapeutics and interventions, yielding better sex-based treatment and prevention strategies for the benefit of all patients.


[1] Committee on Understanding the biology of Sex and Gender Differences; Institute of Medicine. Exploring the biological contributions to human health: Does sex matter? Wizemann TM, Pardue ML, editors. Washington, DC: National Academy Press; 2001. Available from:
[2] Miller VM. Why are sex and gender important to basic physiology and translational and individualized medicine? Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H781-8. DOI: 10.1152/ajpheart.00994.2013
[3] Miller VM, Reckelhoff JF, Sieck GC. Physiology's impact: stop ignoring the obvious-sex matters!. Physiology (Bethesda). 2014 Jan;29(1):4-5. DOI: 10.1152/physiol.00064.2013
[4] Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014 May 15;509(7500):282-3. DOI: 10.1038/509282a
[5] Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon. 2003 Feb;49(2):53-70. DOI: 10.1067/mda.2003.7
[6] Foxman B, Klemstine KL, Brown PD. Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality. Ann Epidemiol. 2003 Feb;13(2):144-50. DOI: 10.1016/S1047-2797(02)00272-7
[7] Efstathiou SP, Pefanis AV, Tsioulos DI, Zacharos ID, Tsiakou AG, Mitromaras AG, Mastorantonakis SE, Kanavaki SN, Mountokalakis TD. Acute pyelonephritis in adults: prediction of mortality and failure of treatment. Arch Intern Med. 2003 May;163(10):1206-12. DOI: 10.1001/archinte.163.10.1206
[8] Nicolle LE, Friesen D, Harding GK, Roos LL. Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin. Clin Infect Dis. 1996 Jun;22(6):1051-6. DOI: 10.1093/clinids/22.6.1051
[9] Ki M, Park T, Choi B, Foxman B. The epidemiology of acute pyelonephritis in South Korea, 1997-1999. Am J Epidemiol. 2004 Nov;160(10):985-93. DOI: 10.1093/aje/kwh308
[10] Spencer JD, Schwaderer AL, Becknell B, Watson J, Hains DS. The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol. 2014 Jul;29(7):1139-49. DOI: 10.1007/s00467-013-2513-9
[11] Olson PD, Hunstad DA. Subversion of Host Innate Immunity by Uropathogenic Escherichia coli. Pathogens. 2016 Jan 4;5(1). pii: E2. DOI: 10.3390/pathogens5010002
[12] Godaly G, Ambite I, Svanborg C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis. 2015 Feb;28(1):88-96. DOI: 10.1097/QCO.0000000000000127
[13] O'Brien VP, Hannan TJ, Schaeffer AJ, Hultgren SJ. Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis. 2015 Feb;28(1):97-105. DOI: 10.1097/QCO.0000000000000130
[14] Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents. 2001 Apr;17(4):259-68. DOI: 10.1016/S0924-8579(00)00350-2
[15] Hooton TM, Scholes D, Stapleton AE, Roberts PL, Winter C, Gupta K, Samadpour M, Stamm WE. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med. 2000 Oct;343(14):992-7. DOI: 10.1056/NEJM200010053431402
[16] Nicolle LE, Harding GK, Preiksaitis J, Ronald AR. The association of urinary tract infection with sexual intercourse. J Infect Dis. 1982 Nov;146(5):579-83. DOI: 10.1093/infdis/146.5.579
[17] Kunin CM, Polyak F, Postel E. Periurethral bacterial flora in women. Prolonged intermittent colonization with Escherichia coli. JAMA. 1980 Jan;243(2):134-9. DOI: 10.1001/jama.1980.03300280032024
[18] Koff SA, Wagner TT, Jayanthi VR. The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol. 1998 Sep;160(3 Pt 2):1019-22. DOI: 10.1016/S0022-5347(01)62686-7
[19] Schneeberger C, Kazemier BM, Geerlings SE. Asymptomatic bacteriuria and urinary tract infections in special patient groups: women with diabetes mellitus and pregnant women. Curr Opin Infect Dis. 2014 Feb;27(1):108-14. DOI: 10.1097/QCO.0000000000000028
[20] Rosen DA, Hung CS, Kline KA, Hultgren SJ. Streptozocin-induced diabetic mouse model of urinary tract infection. Infect Immun. 2008 Sep;76(9):4290-8. DOI: 10.1128/IAI.00255-08
[21] Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 2010 Dec;7(12):653-60. DOI: 10.1038/nrurol.2010.190
[22] Visser VE, Hall RT. Urine culture in the evaluation of suspected neonatal sepsis. J Pediatr. 1979 Apr;94(4):635-8. DOI: 10.1016/S0022-3476(79)80040-2
[23] Tamim MM, Alesseh H, Aziz H. Analysis of the efficacy of urine culture as part of sepsis evaluation in the premature infant. Pediatr Infect Dis J. 2003 Sep;22(9):805-8. DOI: 10.1097/01.inf.0000083822.31857.43
[24] Ismaili K, Lolin K, Damry N, Alexander M, Lepage P, Hall M. Febrile urinary tract infections in 0- to 3-month-old infants: a prospective follow-up study. J Pediatr. 2011 Jan;158(1):91-4. DOI: 10.1016/j.jpeds.2010.06.053
[25] Park S, Han JY, Kim KS. Risk factors for recurrent urinary tract infection in infants with vesicoureteral reflux during prophylactic treatment: effect of delayed contrast passage on voiding cystourethrogram. Urology. 2011 Jul;78(1):170-3. DOI: 10.1016/j.urology.2010.12.023
[26] Wong SN, Tse NK, Lee KP, Yuen SF, Leung LC, Pau BC, Chan WK, Lee KW, Cheung HM, Chim S, Yip CM. Evaluating different imaging strategies in children after first febrile urinary tract infection. Pediatr Nephrol. 2010 Oct;25(10):2083-91. DOI: 10.1007/s00467-010-1569-z
[27] Winberg J, Andersen HJ, Bergström T, Jacobsson B, Larson H, Lincoln K. Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand Suppl. 1974;(252):1-20. DOI: 10.1111/j.1651-2227.1974.tb05718.x
[28] Wettergren B, Jodal U, Jonasson G. Epidemiology of bacteriuria during the first year of life. Acta Paediatr Scand. 1985 Nov;74(6):925-33. DOI: 10.1111/j.1651-2227.1985.tb10059.x
[29] Ginsburg CM, McCracken GH Jr. Urinary tract infections in young infants. Pediatrics. 1982 Apr;69(4):409-12. DOI: 10.1016/S0022-5347(17)53088-8
[30] Kanellopoulos TA, Salakos C, Spiliopoulou I, Ellina A, Nikolakopoulou NM, Papanastasiou DA. First urinary tract infection in neonates, infants and young children: a comparative study. Pediatr Nephrol. 2006 Aug;21(8):1131-7. DOI: 10.1007/s00467-006-0158-7
[31] Bonadio W, Maida G. Urinary tract infection in outpatient febrile infants younger than 30 days of age: a 10-year evaluation. Pediatr Infect Dis J. 2014 Apr;33(4):342-4. DOI: 10.1097/INF.0000000000000110
[32] Arshad M, Seed PC. Urinary tract infections in the infant. Clin Perinatol. 2015 Mar;42(1):17-28, vii. DOI: 10.1016/j.clp.2014.10.003
[33] Milas V, Puseljić S, Stimac M, Dobrić H, Lukić G. Urinary tract infection (UTI) in newborns: risk factors, identification and prevention of consequences. Coll Antropol. 2013 Sep;37(3):871-6.
[34] Khalesi N, Khosravi N, Jalali A, Amini L. Evaluation of maternal urinary tract infection as a potential risk factor for neonatal urinary tract infection. J Family Reprod Health. 2014 Jun;8(2):59-62.
[35] Magliano E, Grazioli V, Deflorio L, Leuci AI, Mattina R, Romano P, Cocuzza CE. Gender and age-dependent etiology of community-acquired urinary tract infections. ScientificWorldJournal. 2012;2012:349597. DOI: 10.1100/2012/349597
[36] Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am. 2003 Jun;17(2):227-41. DOI: 10.1016/S0891-5520(03)00005-9
[37] Wenninger K, Heiman JR, Rothman I, Berghuis JP, Berger RE. Sickness impact of chronic nonbacterial prostatitis and its correlates. J Urol. 1996 Mar;155(3):965-8. DOI: 10.1016/S0022-5347(01)66359-6
[38] Benway BM, Moon TD. Bacterial prostatitis. Urol Clin North Am. 2008 Feb;35(1):23-32; v. DOI: 10.1016/j.ucl.2007.09.008
[39] Schaeffer AJ, Nicolle LE. CLINICAL PRACTICE. Urinary Tract Infections in Older Men. N Engl J Med. 2016 Feb;374(6):562-71. DOI: 10.1056/NEJMcp1503950
[40] Domingue GJ Sr, Hellstrom WJ. Prostatitis. Clin Microbiol Rev. 1998 Oct;11(4):604-13.
[41] Sun TT, Zhao H, Provet J, Aebi U, Wu XR. Formation of asymmetric unit membrane during urothelial differentiation. Mol Biol Rep. 1996;23(1):3-11. DOI: 10.1007/BF00357068
[42] Zhou G, Mo WJ, Sebbel P, Min G, Neubert TA, Glockshuber R, Wu XR, Sun TT, Kong XP. Uroplakin Ia is the urothelial receptor for uropathogenic Escherichia coli: evidence from in vitro FimH binding. J Cell Sci. 2001 Nov;114(Pt 22):4095-103.
[43] Min G, Stolz M, Zhou G, Liang F, Sebbel P, Stoffler D, Glockshuber R, Sun TT, Aebi U, Kong XP. Localization of uroplakin Ia, the urothelial receptor for bacterial adhesin FimH, on the six inner domains of the 16 nm urothelial plaque particle. J Mol Biol. 2002 Apr;317(5):697-706. DOI: 10.1006/jmbi.2002.5442
[44] Song J, Bishop BL, Li G, Duncan MJ, Abraham SN. TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe. 2007 Jun;1(4):287-98. DOI: 10.1016/j.chom.2007.05.007
[45] Wright KJ, Seed PC, Hultgren SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell Microbiol. 2007 Sep;9(9):2230-41. DOI: 10.1111/j.1462-5822.2007.00952.x
[46] Eto DS, Gordon HB, Dhakal BK, Jones TA, Mulvey MA. Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cell Microbiol. 2008 Dec;10(12):2553-67. DOI: 10.1111/j.1462-5822.2008.01229.x
[47] Schilling JD, Mulvey MA, Vincent CD, Lorenz RG, Hultgren SJ. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol. 2001 Jan;166(2):1148-55. DOI: 10.4049/jimmunol.166.2.1148
[48] Berry RE, Klumpp DJ, Schaeffer AJ. Urothelial cultures support intracellular bacterial community formation by uropathogenic Escherichia coli. Infect Immun. 2009 Jul;77(7):2762-72. DOI: 10.1128/IAI.00323-09
[49] Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J. 2000 Jun;19(12):2803-12. DOI: 10.1093/emboj/19.12.2803
[50] Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. Intracellular bacterial biofilm-like pods in urinary tract infections. Science. 2003 Jul;301(5629):105-7. DOI: 10.1126/science.1084550
[51] Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun. 2001 Jul;69(7):4572-9. DOI: 10.1128/IAI.69.7.4572-4579.2001
[52] Eto DS, Jones TA, Sundsbak JL, Mulvey MA. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog. 2007 Jul;3(7):e100. DOI: 10.1371/journal.ppat.0030100
[53] Duncan MJ, Li G, Shin JS, Carson JL, Abraham SN. Bacterial penetration of bladder epithelium through lipid rafts. J Biol Chem. 2004 Apr;279(18):18944-51. DOI: 10.1074/jbc.M400769200
[54] Bishop BL, Duncan MJ, Song J, Li G, Zaas D, Abraham SN. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat Med. 2007 May;13(5):625-30. DOI: 10.1038/nm1572
[55] Eto DS, Sundsbak JL, Mulvey MA. Actin-gated intracellular growth and resurgence of uropathogenic Escherichia coli. Cell Microbiol. 2006 Apr;8(4):704-17. DOI: 10.1111/j.1462-5822.2006.00691.x
[56] Martinez JJ, Hultgren SJ. Requirement of Rho-family GTPases in the invasion of Type 1-piliated uropathogenic Escherichia coli. Cell Microbiol. 2002 Jan;4(1):19-28. DOI: 10.1046/j.1462-5822.2002.00166.x
[57] Doye A, Mettouchi A, Bossis G, Clément R, Buisson-Touati C, Flatau G, Gagnoux L, Piechaczyk M, Boquet P, Lemichez E. CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell. 2002 Nov 15;111(4):553-64. DOI: 10.1016/S0092-8674(02)01132-7
[58] Miyazaki J, Ba-Thein W, Kumao T, Obata Yasuoka M, Akaza H, Hayshi H. Type 1, P and S fimbriae, and afimbrial adhesin I are not essential for uropathogenic Escherichia coli to adhere to and invade bladder epithelial cells. FEMS Immunol Med Microbiol. 2002 Mar;33(1):23-6. DOI: 10.1111/j.1574-695X.2002.tb00567.x
[59] Terada N, Ohno N, Saitoh S, Saitoh Y, Fujii Y, Kondo T, Katoh R, Chan C, Abraham SN, Ohno S. Involvement of dynamin-2 in formation of discoid vesicles in urinary bladder umbrella cells. Cell Tissue Res. 2009 Jul;337(1):91-102. DOI: 10.1007/s00441-009-0804-z
[60] Szabados F, Kleine B, Anders A, Kaase M, Sakinç T, Schmitz I, Gatermann S. Staphylococcus saprophyticus ATCC 15305 is internalized into human urinary bladder carcinoma cell line 5637. FEMS Microbiol Lett. 2008 Aug;285(2):163-9. DOI: 10.1111/j.1574-6968.2008.01218.x
[61] Rosen DA, Pinkner JS, Jones JM, Walker JN, Clegg S, Hultgren SJ. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect Immun. 2008 Jul;76(7):3337-45. DOI: 10.1128/IAI.00090-08
[62] Mulvey MA, Lopez-Boado YS, Wilson CL, Roth R, Parks WC, Heuser J, Hultgren SJ. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science. 1998 Nov;282(5393):1494-7. DOI: 10.1126/science.282.5393.1494
[63] Mysorekar IU, Mulvey MA, Hultgren SJ, Gordon JI. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J Biol Chem. 2002 Mar;277(9):7412-9. DOI: 10.1074/jbc.M110560200
[64] Justice SS, Hunstad DA, Seed PC, Hultgren SJ. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc Natl Acad Sci USA. 2006 Dec;103(52):19884-9. DOI: 10.1073/pnas.0606329104
[65] Horvath DJ Jr, Li B, Casper T, Partida-Sanchez S, Hunstad DA, Hultgren SJ, Justice SS. Morphological plasticity promotes resistance to phagocyte killing of uropathogenic Escherichia coli. Microbes Infect. 2011 May;13(5):426-37. DOI: 10.1016/j.micinf.2010.12.004
[66] Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 2007 Dec;4(12):e329. DOI: 10.1371/journal.pmed.0040329
[67] Robino L, Scavone P, Araujo L, Algorta G, Zunino P, Vignoli R. Detection of intracellular bacterial communities in a child with Escherichia coli recurrent urinary tract infections. Pathog Dis. 2013 Aug;68(3):78-81. DOI: 10.1111/2049-632X.12047
[68] Olson PD, Hruska KA, Hunstad DA. Androgens Enhance Male Urinary Tract Infection Severity in a New Model. J Am Soc Nephrol. 2016 Jun;27(6):1625-34. DOI: 10.1681/ASN.2015030327
[69] Robino L, Scavone P, Araujo L, Algorta G, Zunino P, Pírez MC, Vignoli R. Intracellular bacteria in the pathogenesis of Escherichia coli urinary tract infection in children. Clin Infect Dis. 2014 Dec;59(11):e158-64. DOI: 10.1093/cid/ciu634
[70] Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med. 1989 Jan 15;110(2):138-50. DOI: 10.7326/0003-4819-110-2-138
[71] Singh-Grewal D, Macdessi J, Craig J. Circumcision for the prevention of urinary tract infection in boys: a systematic review of randomised trials and observational studies. Arch Dis Child. 2005 Aug;90(8):853-8. DOI: 10.1136/adc.2004.049353
[72] Wiswell TE, Roscelli JD. Corroborative evidence for the decreased incidence of urinary tract infections in circumcised male infants. Pediatrics. 1986 Jul;78(1):96-9. DOI: 10.1016/S0022-5347(17)45343-2
[73] Wiswell TE, Smith FR, Bass JW. Decreased incidence of urinary tract infections in circumcised male infants. Pediatrics. 1985 May;75(5):901-3. DOI: 10.1016/S0022-5347(17)47483-0
[74] Spach DH, Stapleton AE, Stamm WE. Lack of circumcision increases the risk of urinary tract infection in young men. JAMA. 1992 Feb;267(5):679-81. DOI: 10.1001/jama.1992.03480050083029
[75] Siroky MB. Pathogenesis of bacteriuria and infection in the spinal cord injured patient. Am J Med. 2002 Jul 8;113 Suppl 1A:67S-79S. DOI: 10.1016/S0002-9343(02)01061-6
[76] Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar;52(5):e103-20. DOI: 10.1093/cid/ciq257
[77] Lipsky BA. Prostatitis and urinary tract infection in men: what's new; what's true? Am J Med. 1999 Mar;106(3):327-34. DOI: 10.1016/S0002-9343(99)00017-0
[78] Nicolle LE. A practical guide to antimicrobial management of complicated urinary tract infection. Drugs Aging. 2001;18(4):243-54.
[79] Drekonja DM, Johnson JR. Urinary tract infections. Prim Care. 2008 Jun;35(2):345-67, vii. DOI: 10.1016/j.pop.2008.01.001
[80] Drekonja DM, Rector TS, Cutting A, Johnson JR. Urinary tract infection in male veterans: treatment patterns and outcomes. JAMA Intern Med. 2013 Jan;173(1):62-8. DOI: 10.1001/2013.jamainternmed.829
[81] van Nieuwkoop C, van't Wout JW, Assendelft WJ, Elzevier HW, Leyten EM, Koster T, Wattel-Louis GH, Delfos NM, Ablij HC, Kuijper EJ, Pander J, Blom JW, Spelt IC, van Dissel JT. Treatment duration of febrile urinary tract infection (FUTIRST trial): a randomized placebo-controlled multicenter trial comparing short (7 days) antibiotic treatment with conventional treatment (14 days). BMC Infect Dis. 2009 Aug;9:131. DOI: 10.1186/1471-2334-9-131
[82] Sonnex C. Influence of ovarian hormones on urogenital infection. Sex Transm Infect. 1998 Feb;74(1):11-9. DOI: 10.1136/sti.74.1.11
[83] Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. Estrogenic modulation of uropathogenic Escherichia coli infection pathogenesis in a murine menopause model. Infect Immun. 2013 Mar;81(3):733-9. DOI: 10.1128/IAI.01234-12
[84] Lüthje P, Brauner H, Ramos NL, Ovregaard A, Gläser R, Hirschberg AL, Aspenström P, Brauner A. Estrogen supports urothelial defense mechanisms. Sci Transl Med. 2013 Jun;5(190):190ra80. DOI: 10.1126/scitranslmed.3005574
[85] Curran EM, Tassell AH, Judy BM, Nowicki B, Montgomery-Rice V, Estes DM, Nowicki S. Estrogen increases menopausal host susceptibility to experimental ascending urinary-tract infection. J Infect Dis. 2007 Mar;195(5):680-3. DOI: 10.1086/511275
[86] Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005131. DOI: 10.1002/14651858.CD005131.pub2
[87] Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog. 2010 Aug 12;6(8):e1001042. DOI: 10.1371/journal.ppat.1001042
[88] Hannan TJ, Totsika M, Mansfield KJ, Moore KH, Schembri MA, Hultgren SJ. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev. 2012 May;36(3):616-48. DOI: 10.1111/j.1574-6976.2012.00339.x
[89] Robinson DP, Lorenzo ME, Jian W, Klein SL. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog. 2011 Jul;7(7):e1002149. DOI: 10.1371/journal.ppat.1002149
[90] Kadioglu A, Cuppone AM, Trappetti C, List T, Spreafico A, Pozzi G, Andrew PW, Oggioni MR. Sex-based differences in susceptibility to respiratory and systemic pneumococcal disease in mice. J Infect Dis. 2011 Dec;204(12):1971-9. DOI: 10.1093/infdis/jir657
[91] Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000 Aug;24(6):627-38. DOI: 10.1016/S0149-7634(00)00027-0
[92] Billington WD. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol. 2003 Oct;60(1):1-11. DOI: 10.1016/S0165-0378(03)00083-4
[93] Gleicher N, Barad DH. Gender as risk factor for autoimmune diseases. J Autoimmun. 2007 Feb;28(1):1-6. DOI: 10.1016/j.jaut.2006.12.004
[94] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997 Sep;84(3):223-43.
[95] Pollitzer E. Biology: Cell sex matters. Nature. 2013 Aug;500(7460):23-4. DOI: 10.1038/500023a
[96] Cahill L. A half-truth is a whole lie: on the necessity of investigating sex influences on the brain. Endocrinology. 2012 Jun;153(6):2541-3. DOI: 10.1210/en.2011-2167
[97] den Heijer CD, Penders J, Donker GA, Bruggeman CA, Stobberingh EE. The importance of gender-stratified antibiotic resistance surveillance of unselected uropathogens: a Dutch Nationwide Extramural Surveillance study. PLoS ONE. 2013;8(3):e60497. DOI: 10.1371/journal.pone.0060497