DOI QR코드

DOI QR Code

A Dynamic Interplay of Innate Immune Responses During Urinary Tract Infection

  • Received : 2024.05.16
  • Accepted : 2024.07.17
  • Published : 2024.08.31

Abstract

Urinary tract infections (UTIs) represent one of the most prevalent bacterial infections globally, manifesting in diverse clinical phenotypes with varying degrees of severity and complications. The mechanisms underlying UTIs are gradually being elucidated, leading to an enhanced understanding of the immune responses involved. Innate immune cells play a crucial defensive role against uropathogenic bacteria through various mechanisms. Despite their significant contributions to host defense, these cells often fail to achieve complete clearance of uropathogens, necessitating the frequent prescription of antibiotics for UTI patients. However, the persistence of infections and related pathological symptoms in the absence of innate immune cells in animal models underscore the importance of innate immunity in UTIs. Therefore, the host protective functions of innate immune cells, including neutrophils, macrophages, mast cells, NK cells, innate lymphoid cells, and γδ T cells, are delicately coordinated and timely regulated by a variety of cytokines to ensure successful pathogen clearance.

Keywords

Acknowledgement

Hae Woong Choi was supported by the National Research Foundation of Korea grants (NRF-2020R1C1C1003257 and RS-2023-00221182) and the internal grant of Korea University. The figure was created with BioRender.com.

References

  1. Klein RD, Hultgren SJ. Urinary tract infections: microbial pathogenesis, host-pathogen interactions and new treatment strategies. Nat Rev Microbiol 2020;18:211-226.  https://doi.org/10.1038/s41579-020-0324-0
  2. Boon HA, Struyf T, Crevecoeur J, Delvaux N, Van Pottelbergh G, Vaes B, Van den Bruel A, Verbakel JY. Incidence rates and trends of childhood urinary tract infections and antibiotic prescribing: registry-based study in general practices (2000 to 2020). BMC Prim Care 2022;23:177.
  3. Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000;182:1177-1182. https://doi.org/10.1086/315827
  4. Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am 2014;28:1-13. https://doi.org/10.1016/j.idc.2013.09.003
  5. 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;114:4095-4103. https://doi.org/10.1242/jcs.114.22.4095
  6. Jafari NV, Rohn JL. The urothelium: a multi-faceted barrier against a harsh environment. Mucosal Immunol 2022;15:1127-1142. https://doi.org/10.1038/s41385-022-00565-0
  7. Bowyer GS, Loudon KW, Suchanek O, Clatworthy MR. Tissue immunity in the bladder. Annu Rev Immunol 2022;40:499-523. https://doi.org/10.1146/annurev-immunol-101220-032117
  8. Wu J, Abraham SN. The roles of t cells in bladder pathologies. Trends Immunol 2021;42:248-260. https://doi.org/10.1016/j.it.2021.01.003
  9. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011;11:519-531. https://doi.org/10.1038/nri3024
  10. Shrestha S, Hong CW. Extracellular mechanisms of neutrophils in immune cell crosstalk. Immune Netw 2023;23:e38.
  11. Chakrabarti S, Patel KD. Regulation of matrix metalloproteinase-9 release from IL-8-stimulated human neutrophils. J Leukoc Biol 2005;78:279-288. https://doi.org/10.1189/jlb.1004612
  12. Agace WW, Patarroyo M, Svensson M, Carlemalm E, Svanborg C. Escherichia coli induces transuroepithelial neutrophil migration by an intercellular adhesion molecule-1-dependent mechanism. Infect Immun 1995;63:4054-4062. https://doi.org/10.1128/iai.63.10.4054-4062.1995
  13. Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, Segal AW. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 2002;416:291-297. https://doi.org/10.1038/416291a
  14. Segal AW. How neutrophils kill microbes. Annu Rev Immunol 2005;23:197-223. https://doi.org/10.1146/annurev.immunol.23.021704.115653
  15. Isaacson B, Baron M, Yamin R, Bachrach G, Levi-Schaffer F, Granot Z, Mandelboim O. The inhibitory receptor CD300a is essential for neutrophil-mediated clearance of urinary tract infection in mice. Eur J Immunol 2021;51:2218-2224. https://doi.org/10.1002/eji.202049006
  16. Jaillon S, Moalli F, Ragnarsdottir B, Bonavita E, Puthia M, Riva F, Barbati E, Nebuloni M, Cvetko Krajinovic L, Markotic A, et al. The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. Immunity 2014;40:621-632. https://doi.org/10.1016/j.immuni.2014.02.015
  17. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532-1535. https://doi.org/10.1126/science.1092385
  18. Neubert E, Meyer D, Rocca F, Gunay G, Kwaczala-Tessmann A, Grandke J, Senger-Sander S, Geisler C, Egner A, Schon MP, et al. Chromatin swelling drives neutrophil extracellular trap release. Nat Commun 2018;9:3767.
  19. Lewis HD, Liddle J, Coote JE, Atkinson SJ, Barker MD, Bax BD, Bicker KL, Bingham RP, Campbell M, Chen YH, et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol 2015;11:189-191. https://doi.org/10.1038/nchembio.1735
  20. Ou Q, Fang JQ, Zhang ZS, Chi Z, Fang J, Xu DY, Lu KZ, Qian MQ, Zhang DY, Guo JP, et al. TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4. Nat Commun 2021;12:3481.
  21. Yu Y, Kwon K, Tsitrin T, Bekele S, Sikorski P, Nelson KE, Pieper R. Characterization of early-phase neutrophil extracellular traps in urinary tract infections. PLoS Pathog 2017;13:e1006151.
  22. Krivosikova K, Supcikova N, Gaal Kovalcikova A, Janko J, Pastorek M, Celec P, Podracka L, Tothova L. Neutrophil extracellular traps in urinary tract infection. Front Pediatr 2023;11:1154139.
  23. Mora-Bau G, Platt AM, van Rooijen N, Randolph GJ, Albert ML, Ingersoll MA. Macrophages subvert adaptive immunity to urinary tract infection. PLoS Pathog 2015;11:e1005044.
  24. Wang AS, Steers NJ, Parab AR, Gachon F, Sweet MJ, Mysorekar IU. Timing is everything: impact of development, ageing and circadian rhythm on macrophage functions in urinary tract infections. Mucosal Immunol 2022;15:1114-1126. https://doi.org/10.1038/s41385-022-00558-z
  25. Lacerda Mariano L, Rousseau M, Varet H, Legendre R, Gentek R, Saenz Coronilla J, Bajenoff M, Gomez Perdiguero E, Ingersoll MA. Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder. Sci Adv 2020;6:eabc5739.
  26. Mintz D, Salamon H, Mintz M, Rosenshine I, Shpigel NY. Intraepithelial neutrophils in mammary, urinary and gall bladder infections. Vet Res 2019;50:56.
  27. Agace W, Hedges S, Andersson U, Andersson J, Ceska M, Svanborg C. Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect Immun 1993;61:602-609. https://doi.org/10.1128/iai.61.2.602-609.1993
  28. Vega-Perez A, Villarrubia LH, Godio C, Gutierrez-Gonzalez A, Feo-Lucas L, Ferriz M, Martinez-Puente N, Alcain J, Mora A, Sabio G, et al. Resident macrophage-dependent immune cell scaffolds drive antibacterial defense in the peritoneal cavity. Immunity 2021;54:2578-2594.e5. https://doi.org/10.1016/j.immuni.2021.10.007
  29. De Filippo K, Henderson RB, Laschinger M, Hogg N. Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways. J Immunol 2008;180:4308-4315. https://doi.org/10.4049/jimmunol.180.6.4308
  30. Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C, Pohl JM, Maurice NJ, Thiebes S, Lorenz K, et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 2014;156:456-468. https://doi.org/10.1016/j.cell.2014.01.006
  31. Carey AJ, Sullivan MJ, Duell BL, Crossman DK, Chattopadhyay D, Brooks AJ, Tan CK, Crowley M, Sweet MJ, Schembri MA, et al. Uropathogenic Escherichia coli engages cd14-dependent signaling to enable bladder-macrophage-dependent control of acute urinary tract infection. J Infect Dis 2016;213:659-668. https://doi.org/10.1093/infdis/jiv424
  32. Bottek J, Soun C, Lill JK, Dixit A, Thiebes S, Beerlage AL, Horstmann M, Urbanek A, Heuer H, Uszkoreit J, et al. Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder. Mucosal Immunol 2020;13:702-714. https://doi.org/10.1038/s41385-020-0269-7
  33. Owusu-Boaitey N, Bauckman KA, Zhang T, Mysorekar IU. Macrophagic control of the response to uropathogenic E. coli infection by regulation of iron retention in an IL-6-dependent manner. Immun Inflamm Dis 2016;4:413-426. https://doi.org/10.1002/iid3.123
  34. Smith J, Tan JK, Moro C. Mast cell distribution and prevalence in the murine urinary bladder. BMC Urol 2024;24:51.
  35. Choi HW, Bowen SE, Miao Y, Chan CY, Miao EA, Abrink M, Moeser AJ, Abraham SN. Loss of bladder epithelium induced by cytolytic mast cell granules. Immunity 2016;45:1258-1269. https://doi.org/10.1016/j.immuni.2016.11.003
  36. Wu Z, Li Y, Liu Q, Liu Y, Chen L, Zhao H, Guo H, Zhu K, Zhou N, Chai TC, et al. Pyroptosis engagement and bladder urothelial cell-derived exosomes recruit mast cells and induce barrier dysfunction of bladder urothelium after uropathogenic E. coli infection. Am J Physiol Cell Physiol 2019;317:C544-C555. https://doi.org/10.1152/ajpcell.00102.2019
  37. Justice SS, Hung C, Theriot JA, Fletcher DA, Anderson GG, Footer MJ, Hultgren SJ. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci U S A 2004;101:1333-1338. https://doi.org/10.1073/pnas.0308125100
  38. Chan CY, St John AL, Abraham SN. Mast cell interleukin-10 drives localized tolerance in chronic bladder infection. Immunity 2013;38:349-359. https://doi.org/10.1016/j.immuni.2012.10.019
  39. Gentek R, Ghigo C, Hoeffel G, Bulle MJ, Msallam R, Gautier G, Launay P, Chen J, Ginhoux F, Bajenoff M. Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells. Immunity 2018;48:1160-1171.e5. https://doi.org/10.1016/j.immuni.2018.04.025
  40. Tauber M, Basso L, Martin J, Bostan L, Pinto MM, Thierry GR, Houmadi R, Serhan N, Loste A, Bleriot C, et al. Landscape of mast cell populations across organs in mice and humans. J Exp Med 2023;220:e20230570.
  41. Gonzales CM, Williams CB, Calderon VE, Huante MB, Moen ST, Popov VL, Baze WB, Peterson JW, Endsley JJ. Antibacterial role for natural killer cells in host defense to Bacillus anthracis. Infect Immun 2012;80:234-242. https://doi.org/10.1128/IAI.05439-11
  42. Lu CC, Wu TS, Hsu YJ, Chang CJ, Lin CS, Chia JH, Wu TL, Huang TT, Martel J, Ojcius DM, et al. NK cells kill mycobacteria directly by releasing perforin and granulysin. J Leukoc Biol 2014;96:1119-1129. https://doi.org/10.1189/jlb.4A0713-363RR
  43. Katz P, Yeager H Jr, Whalen G, Evans M, Swartz RP, Roecklein J. Natural killer cell-mediated lysis of Mycobacterium-avium complex-infected monocytes. J Clin Immunol 1990;10:71-77. https://doi.org/10.1007/BF00917500
  44. Gur C, Coppenhagen-Glazer S, Rosenberg S, Yamin R, Enk J, Glasner A, Bar-On Y, Fleissig O, Naor R, Abed J, et al. Natural killer cell-mediated host defense against uropathogenic E. coli is counteracted by bacterial hemolysinA-dependent killing of NK cells. Cell Host Microbe 2013;14:664-674. https://doi.org/10.1016/j.chom.2013.11.004
  45. Isaacson B, Hadad T, Glasner A, Gur C, Granot Z, Bachrach G, Mandelboim O. Stromal cell-derived factor 1 mediates immune cell attraction upon urinary tract infection. Cell Reports 2017;20:40-47.  https://doi.org/10.1016/j.celrep.2017.06.034
  46. Chamoun MN, Sullivan MJ, Goh KG, Acharya D, Ipe DS, Katupitiya L, Gosling D, Peters KM, Sweet MJ, Sester DP, et al. Restriction of chronic Escherichia coli urinary tract infection depends upon T cell-derived interleukin-17, a deficiency of which predisposes to flagella-driven bacterial persistence. FASEB J 2020;34:14572-14587. https://doi.org/10.1096/fj.202000760R
  47. Mian MF, Lauzon NM, Andrews DW, Lichty BD, Ashkar AA. FimH can directly activate human and murine natural killer cells via TLR4. Mol Ther 2010;18:1379-1388. https://doi.org/10.1038/mt.2010.75
  48. Zychlinsky Scharff A, Rousseau M, Lacerda Mariano L, Canton T, Consiglio CR, Albert ML, Fontes M, Duffy D, Ingersoll MA. Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection. JCI Insight 2019;5:e122998.
  49. Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol 2007;7:703-714. https://doi.org/10.1038/nri2154
  50. Elemam NM, Ramakrishnan RK, Hundt JE, Halwani R, Maghazachi AA, Hamid Q. Innate lymphoid cells and natural killer cells in bacterial infections: function, dysregulation, and therapeutic targets. Front Cell Infect Microbiol 2021;11:733564.
  51. Ham J, Shin JW, Ko BC, Kim HY. Targeting the epithelium-derived innate cytokines: from bench to bedside. Immune Netw 2022;22:e11.
  52. Huang J, Fu L, Huang J, Zhao J, Zhang X, Wang W, Liu Y, Sun B, Qiu J, Hu X, et al. Group 3 innate lymphoid cells protect the host from the uropathogenic Escherichia coli infection in the bladder. Adv Sci (Weinh) 2022;9:e2103303.
  53. Riding AM, Loudon KW, Guo A, Ferdinand JR, Lok LSC, Richoz N, Stewart A, Castro-Dopico T, Tuong ZK, Fiancette R, et al. Group 3 innate lymphocytes make a distinct contribution to type 17 immunity in bladder defence. iScience 2022;25:104660.
  54. Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol 2018;55:379-390. https://doi.org/10.1007/s12016-018-8702-3
  55. Logadottir Y, Delbro D, Fall M, Gjertsson I, Jirholt P, Lindholm C, Peeker R. Cytokine expression in patients with bladder pain syndrome/interstitial cystitis ESSIC type 3C. J Urol 2014;192:1564-1568. https://doi.org/10.1016/j.juro.2014.04.099
  56. Bhide A, Tailor V, Khullar V. Interstitial cystitis/bladder pain syndrome and recurrent urinary tract infection and the potential role of the urinary microbiome. Post Reprod Health 2020;26:87-90. https://doi.org/10.1177/2053369120936426
  57. Sivick KE, Schaller MA, Smith SN, Mobley HL. The innate immune response to uropathogenic Escherichia coli involves IL-17A in a murine model of urinary tract infection. J Immunol 2010;184:2065-2075. https://doi.org/10.4049/jimmunol.0902386
  58. Jones-Carson J, Balish E, Uehling DT. Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J Urol 1999;161:338-341. https://doi.org/10.1016/S0022-5347(01)62142-6
  59. Minagawa S, Ohyama C, Hatakeyama S, Tsuchiya N, Kato T, Habuchi T. Activation of natural killer T cells by α-galactosylceramide mediates clearance of bacteria in murine urinary tract infection. J Urol 2005;173:2171-2174. https://doi.org/10.1097/01.ju.0000158122.16046.68
  60. Nieuwenhuis EE, Matsumoto T, Exley M, Schleipman RA, Glickman J, Bailey DT, Corazza N, Colgan SP, Onderdonk AB, Blumberg RS. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat Med 2002;8:588-593. https://doi.org/10.1038/nm0602-588
  61. Naskar M, Parekh VP, Abraham MA, Alibasic Z, Kim MJ, Suk G, Noh JH, Ko KY, Lee J, Kim C, et al. α-Hemolysin promotes uropathogenic E. coli persistence in bladder epithelial cells via abrogating bacteria-harboring lysosome acidification. PLoS Pathog 2023;19:e1011388.
  62. Thumbikat P, Berry RE, Zhou G, Billips BK, Yaggie RE, Zaichuk T, Sun TT, Schaeffer AJ, Klumpp DJ. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog 2009;5:e1000415.
  63. Ching C, Schwartz L, Spencer JD, Becknell B. Innate immunity and urinary tract infection. Pediatr Nephrol 2020;35:1183-1192. https://doi.org/10.1007/s00467-019-04269-9
  64. Song J, Abraham SN. TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol 2008;11:66-73. https://doi.org/10.1016/j.mib.2007.12.001
  65. Frendeus B, Wachtler C, Hedlund M, Fischer H, Samuelsson P, Svensson M, Svanborg C. Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation. Mol Microbiol 2001;40:37-51. https://doi.org/10.1046/j.1365-2958.2001.02361.x
  66. Fischer H, Yamamoto M, Akira S, Beutler B, Svanborg C. Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur J Immunol 2006;36:267-277.  https://doi.org/10.1002/eji.200535149
  67. Andersen-Nissen E, Hawn TR, Smith KD, Nachman A, Lampano AE, Uematsu S, Akira S, Aderem A. Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection. J Immunol 2007;178:4717-4720. https://doi.org/10.4049/jimmunol.178.8.4717
  68. Ching CB, Gupta S, Li B, Cortado H, Mayne N, Jackson AR, McHugh KM, Becknell B. Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. Kidney Int 2018;93:1320-1329. https://doi.org/10.1016/j.kint.2017.12.006
  69. Morrison G, Kilanowski F, Davidson D, Dorin J. Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect Immun 2002;70:3053-3060. https://doi.org/10.1128/IAI.70.6.3053-3060.2002
  70. Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB Jr, Ganz T. Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 1998;101:1633-1642. https://doi.org/10.1172/JCI1861
  71. Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I, Hokfelt T, Gudmundsson GH, Gallo RL, Agerberth B, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 2006;12:636-641. https://doi.org/10.1038/nm1407
  72. Spencer JD, Schwaderer AL, Dirosario JD, McHugh KM, McGillivary G, Justice SS, Carpenter AR, Baker PB, Harder J, Hains DS. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int 2011;80:174-180. https://doi.org/10.1038/ki.2011.109
  73. Godaly G, Hang L, Frendeus B, Svanborg C. Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice. J Immunol 2000;165:5287-5294. https://doi.org/10.4049/jimmunol.165.9.5287
  74. Frendeus B, Godaly G, Hang L, Karpman D, Lundstedt AC, Svanborg C. Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart. J Exp Med 2000;192:881-890. https://doi.org/10.1084/jem.192.6.881
  75. 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;13:625-630. https://doi.org/10.1038/nm1572
  76. Miao Y, Li G, Zhang X, Xu H, Abraham SN. A TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 2015;161:1306-1319. https://doi.org/10.1016/j.cell.2015.05.009
  77. Liu YG, Teng YS, Cheng P, Kong H, Lv YP, Mao FY, Wu XL, Hao CJ, Chen W, Yang SM, et al. Abrogation of cathepsin C by Helicobacter pylori impairs neutrophil activation to promote gastric infection. FASEB J 2019;33:5018-5033. https://doi.org/10.1096/fj.201802016RR
  78. Song CH, Kim YH, Naskar M, Hayes BW, Abraham MA, Noh JH, Suk G, Kim MJ, Cho KS, Shin M, et al. Lactobacillus crispatus limits bladder uropathogenic E. coli infection by triggering a host type I interferon response. Proc Natl Acad Sci USA 2022;119:e2117904119.
  79. Demirel I, Persson A, Brauner A, Sarndahl E, Kruse R, Persson K. Activation of NLRP3 by uropathogenic Escherichia coli is associated with IL-1β release and regulation of antimicrobial properties in human neutrophils. Sci Rep 2020;10:21837.
  80. Zec K, Volke J, Vijitha N, Thiebes S, Gunzer M, Kurts C, Engel DR. Neutrophil migration into the infected uroepithelium is regulated by the crosstalk between resident and helper macrophages. Pathogens 2016;5:15.
  81. Regauer S. Mast cell activation syndrome in pain syndromes bladder pain syndrome/interstitial cystitis and vulvodynia. Transl Androl Urol 2016;5:396-397. https://doi.org/10.21037/tau.2016.03.12
  82. Wang X, Liu W, O'Donnell M, Lutgendorf S, Bradley C, Schrepf A, Liu L, Kreder K, Luo Y. Evidence for the role of mast cells in cystitis-associated lower urinary tract dysfunction: a multidisciplinary approach to the study of chronic pelvic pain research network animal model study. PLoS One 2016;11:e0168772.
  83. Belizario JE, Neyra JM, Setubal Destro Rodrigues MF. When and how NK cell-induced programmed cell death benefits immunological protection against intracellular pathogen infection. Innate Immun 2018;24:452-465. https://doi.org/10.1177/1753425918800200
  84. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004;303:1522-1526. https://doi.org/10.1126/science.1094351
  85. Song J, Duncan MJ, Li G, Chan C, Grady R, Stapleton A, Abraham SN. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog 2007;3:e60.
  86. Nagamatsu K, Hannan TJ, Guest RL, Kostakioti M, Hadjifrangiskou M, Binkley J, Dodson K, Raivio TL, Hultgren SJ. Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc Natl Acad Sci USA 2015;112:E871-E880.
  87. Wu J, Bao C, Reinhardt RL, Abraham SN. Local induction of bladder Th1 responses to combat urinary tract infections. Proc Natl Acad Sci USA 2021;118:e2026461118.