Innate Immunity in the Human Female Reproductive Tract: Endocrine Regulation of Endogenous Antimicrobial Protection Against HIV and Other Sexually Transmitted Infections

American Journal of Reproductive Immunology

Volumn 65, Issue 3, 2011, Pages 196-211

  Wira, Charles R ^a   Patel, Mickey V ^a   Ghosh, Mimi ^a   Mukura, Lucy ^a   Fahey, John V ^a  

^a DARTMOUTH MEDICAL SCHOOL   (United States)

Author keywords

Antimicrobials; Female reproductive tract; Innate immunity

Indexed keywords

ALPHA DEFENSIN; ANTIINFECTIVE AGENT; BETA DEFENSIN; CALGRANULIN; CATHELICIDIN; ELAFIN; LACTOFERRIN; LYSOZYME; MACROPHAGE INFLAMMATORY PROTEIN 3ALPHA; PROTEINASE; SECRETORY LEUKOCYTE PROTEINASE INHIBITOR; SEX HORMONE; SURFACTANT PROTEIN A; THROMBOSPONDIN;

ANTIMICROBIAL ACTIVITY; CANDIDA ALBICANS; CHLAMYDIA TRACHOMATIS; EPITHELIUM CELL; FEMALE FERTILITY; FEMALE GENITAL SYSTEM; HERPES SIMPLEX VIRUS; HORMONE RELEASE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOCOMPETENT CELL; INNATE IMMUNITY; LACTOBACILLUS; MENSTRUAL CYCLE; NEISSERIA GONORRHOEAE; NONHUMAN; PATHOGENESIS; POSTMENOPAUSE; PRIORITY JOURNAL; REPRODUCTIVE HEALTH; REVIEW; SEXUALLY TRANSMITTED DISEASE; TRICHOMONAS VAGINALIS; VAGINITIS; WART VIRUS;

ANTI-INFECTIVE AGENTS; ENDOCRINE GLANDS; FEMALE; GENITALIA, FEMALE; GONADAL STEROID HORMONES; HIV INFECTIONS; HIV-1; HUMANS; IMMUNITY, INNATE; MENSTRUAL CYCLE; SEXUALLY TRANSMITTED DISEASES;

EID: 79551619576     PISSN: 10467408     EISSN: 16000897     Source Type: Journal    
DOI: 10.1111/j.1600-0897.2011.00970.x     Document Type: Review

References (158)

1. UNAIDS: AIDS epidemic update 2007.
2. WHO: Global Prevalence and Incidence of Selected Curable Sexually Transmitted Infections: Overview and Estimates. Geneva, World Health Organisation (WHO), 2001.
3. UNAIDS: UNAIDS global report 2009.
4. Greenberg A, Hader S, Masur H, Young A, Skillicorn J, Dieffenbach C: Fighting HIV/AIDS in Washington, D.C. Health Affairs (Millwood) 2009; 28:1677-1687.
5. Shafer WM, Agerberth B, Gumundsson G: Host antimicrobial defence peptides in human disease. In Antimicrobial Peptides and Human Disease, WM Shafer (ed.). Berlin, Heidelberg, Springer, 2006, pp 67-90.
6. Wira CR, Fahey JV: A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle. AIDS 2008; 22:1909-1917.
7. Givan AL, White HD, Stern JE, Colby E, Gosselin EJ, Guyre PM, Wira CR: Flow cytometric analysis of leukocytes in the human female reproductive tract: comparison of fallopian tube, uterus, cervix, and vagina. Am J Reprod Immunol 1997; 38:350-359.
8. Cole AM, Cole AL: Antimicrobial polypeptides are key anti-HIV-1 effector molecules of cervicovaginal host defense. Am J Reprod Immunol 2008; 59:27-34.
9. Shafer WM, Bowdish D, Davidson D, Hancock R: Immunomodulatory properties of defensins and cathelicidins. In Antimicrobial Peptides and Human Disease, WM Shafer (ed.). Berlin, Heidelberg, Springer, 2006, pp 27-66.
10. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347:1151-1160.
11. Singh PK, Tack BF, McCray Jr PB, Welsh MJ: Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am J Physiol Lung Cell Mol Physiol 2000; 279:L799-L805.
12. Klotman ME, Chang TL: Defensins in innate antiviral immunity. Nat Rev Immunol 2006; 6:447-456.
13. Cole AM: Innate host defense of human vaginal and cervical mucosae. Curr Top Microbiol Immunol 2006; 306:199-230.
14. Lehrer RI, Ganz T, Szklarek D, Selsted ME: Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J Clin Invest 1988; 81:1829-1835.
15. Turner J, Cho Y, Dinh NN, Waring AJ, Lehrer RI: Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob Agents Chemother 1998; 42:2206-2214.
16. Daher KA, Selsted ME, Lehrer RI: Direct inactivation of viruses by human granulocyte defensins. J Virol 1986; 60:1068-1074.
17. Chang TL, Vargas Jr J, DelPortillo A, Klotman ME: Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. J Clin Invest 2005; 115:765-773.
18. Hristova K, Selsted ME, White SH: Critical role of lipid composition in membrane permeabilization by rabbit neutrophil defensins. J Biol Chem 1997; 272:24224-24233.
19. Lehrer RI, Lichtenstein AK, Ganz T: Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol 1993; 11:105-128.
20. Klotman ME, Rapista A, Teleshova N, Micsenyi A, Jarvis GA, Lu W, Porter E, Chang TL: Neisseria gonorrhoeae-induced human defensins 5 and 6 increase HIV infectivity: role in enhanced transmission. J Immunol 2008; 180:6176-6185.
21. Quinones-Mateu ME, Lederman MM, Feng Z, Chakraborty B, Weber J, Rangel HR, Marotta ML, Mirza M, Jiang B, Kiser P, Medvik K, Sieg SF, Weinberg A: Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication. AIDS 2003; 17:F39-F48.
22. Sun L, Finnegan CM, Kish-Catalone T, Blumenthal R, Garzino-Demo P, La Terra Maggiore GM, Berrone S, Kleinman C, Wu Z, Abdelwahab S, Lu W, Garzino-Demo A: Human beta-defensins suppress human immunodeficiency virus infection: potential role in mucosal protection. J Virol 2005; 79:14318-14329.
23. Weinberg A, Quinones-Mateu ME, Lederman MM: Role of human beta-defensins in HIV infection. Adv Dent Res 2006; 19:42-48.
24. Doss M, White MR, Tecle T, Hartshorn KL: Human defensins and LL-37 in mucosal immunity. J Leukoc Biol 2010; 87:79-92.
25. Zaiou M, Nizet V, Gallo RL: Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol 2003; 120:810-816.
26. Sorensen OE, Gram L, Johnsen AH, Andersson E, Bangsboll S, Tjabringa GS, Hiemstra PS, Malm J, Egesten A, Borregaard N: Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina. J Biol Chem 2003; 278:28540-28546.
27. Bingle CD, Vyakarnam A: Novel innate immune functions of the whey acidic protein family. Trends Immunol 2008; 29:444-453.
28. Moreau T, Baranger K, Dadé S, Dallet-Choisy S, Guyot N, Zani M-L: Multifaceted roles of human elafin and secretory leukocyte proteinase inhibitor (SLPI), two serine protease inhibitors of the chelonianin family. Biochimie 2008; 90:284-295.
29. Ghosh M, Shen Z, Fahey JV, Cu-Uvin S, Mayer K, Wira CR: Trappin-2/Elafin: a novel innate anti-human immunodeficiency virus-1 molecule of the human female reproductive tract. Immunology 2010; 129:207-219.
30. Iqbal SM, Ball TB, Levinson P, Maranan L, Jaoko W, Wachihi C, Pak BJ, Podust VN, Broliden K, Hirbod T, Kaul R, Plummer FA: Elevated elafin/trappin-2 in the female genital tract is associated with protection against HIV acquisition. AIDS 2009; 23:1669-1677.
31. McNeely TB, Shugars DC, Rosendahl M, Tucker C, Eisenberg SP, Wahl SM: Inhibition of human immunodeficiency virus type 1infectivity by secretory leukocyte protease inhibitor occurs prior to viral reverse transcription. Blood 1997; 90:1141-1149.
32. Ma G, Greenwell-Wild T, Lei K, Jin W, Swisher J, Hardegen N, Wild CT, Wahl SM: Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. J Exp Med 2004; 200:1337-1346.
33. Ibrahim HR, Matsuzaki T, Aoki T: Genetic evidence that antibacterial activity of lysozyme is independent of its catalytic function. FEBS Lett 2001; 506:27-32.
34. Lee-Huang S, Huang PL, Sun Y, Huang PL, Kung H-f, Blithe DL, Chen H-C: Lysozyme and RNases as anti-HIV components in beta-core preparations of human chorionic gonadotropin. Proc Natl Acad Sci USA 1999; 96:2678-2681.
35. Lee-Huang S, Maiorov V, Huang PL, Ng A, Lee HC, Chang YT, Kallenbach N, Chen HC: Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity. Biochemistry 2005; 44:4648-4655.
36. Harmsen MC, Swart PJ, de Bethune MP, Pauwels R, De Clercq E, The TH, Meijer DK: Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. J Infect Dis 1995; 172:380-388.
37. Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, Oppenheim JJ: Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 2003; 74:448-455.
38. Ghosh M, Shen Z, Schaefer TM, Fahey JV, Gupta P, Wira CR: CCL20/MIP3α is a novel anti-HIV-1 molecule of the human female reproductive tract. Am J Reprod Immunol 2009; 62:60-71.
39. Keller MJ, Guzman E, Hazrati E, Kasowitz A, Cheshenko N, Wallenstein S, Cole AL, Cole AM, Profy AT, Wira CR, Hogarty K, Herold BC: PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 2007; 21:467-476.
40. Horne AW, Stock SJ, King AE: Innate immunity and disorders of the female reproductive tract. Reproduction 2008; 135:739-749.
41. Pommerville J: Infectious diseases affecting the reproductive and urinary systems. In Alcamo's Fundamentals of Microbiology: Body Systems, J Pommerville (ed.). Sudbury, MA, Jones & Bartlett Publishers, 2010, pp 814-815.
42. Valore EV, Park CH, Igreti SL, Ganz T: Antimicrobial components of vaginal fluid. Am J Obstet Gynecol 2002; 187:561-568.
43. Moriyama A, Shimoya K, Ogata I, Kimura T, Nakamura T, Wada H, Ohashi K, Azuma C, Saji F, Murata Y: Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle. Mol Hum Reprod 1999; 5:656-661.
44. King AE, Critchley HOD, Sallenave J-M, Kelly RW: Elafin in human endometrium: an antiprotease and antimicrobial molecule expressed during menstruation. J Clin Endocrinol Metab 2003; 88:4426-4431.
45. King AE, Critchley HOD, Kelly RW: Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role. Mol Hum Reprod 2000; 6:191-196.
46. King AE, Wheelhouse N, Cameron S, McDonald SE, Lee KF, Entrican G, Critchley HO, Horne AW: Expression of secretory leukocyte protease inhibitor and elafin in human fallopian tube and in an in-vitro model of Chlamydia trachomatis infection. Hum Reprod 2009; 24:679-686.
47. Mosher WD, Jones J: Use of contraception in the United States: 1982-2008. Vital Health Stat 2010; 23:1-44.
48. Schumacher GFB: Soluble proteins in cervical mucus. In The Biology of the Cervix, RJ Blandau, K Moghissi (eds). Chicago, The University of Chicago Press, 1973, pp 201-233.
49. Shust GF, Cho S, Kim M, Madan RP, Guzman EM, Pollack M, Epstein J, Cohen HW, Keller MJ, Herold BC: Female genital tract secretions inhibit herpes simplex virus infection: correlation with soluble mucosal immune mediators and impact of hormonal contraception. Am J Reprod Immunol 2010; 63:110-119.
50. Fleming DC, King AE, Williams AR, Critchley HO, Kelly RW: Hormonal contraception can suppress natural antimicrobial gene transcription in human endometrium. Fertil Steril 2003; 79:856-863.
51. Mor G, Cardenas I: The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010; 63:425-433.
52. King AE, Paltoo A, Kelly RW, Sallenave JM, Bocking AD, Challis JR: Expression of natural antimicrobials by human placenta and fetal membranes. Placenta 2007; 28:161-169.
53. Xu J, Holzman CB, Arvidson CG, Chung H, Goepfert AR: Midpregnancy vaginal fluid defensins, bacterial vaginosis, and risk of preterm delivery. Obstet Gynecol 2008; 112:524-531.
54. Balu RB, Savitz DA, Ananth CV, Hartmann KE, Miller WC, Thorp JM, Heine RP: Bacterial vaginosis and vaginal fluid defensins during pregnancy. Am J Obstet Gynecol 2002; 187:1267-1271.
55. Simhan HN, Anderson BL, Krohn MA, Heine RP, Martinez de Tejada B, Landers DV, Hillier SL: Host immune consequences of asymptomatic Trichomonas vaginalis infection in pregnancy. Am J Obstet Gynecol 2007; 196:59.e1-59.e5.
56. King AE, Kelly RW, Sallenave JM, Bocking AD, Challis JR: Innate immune defences in the human uterus during pregnancy. Placenta 2007; 28:1099-1106.
57. Draper D, Donohoe W, Mortimer L, Heine RP: Cysteine proteases of Trichomonas vaginalis degrade secretory leukocyte protease inhibitor. J Infect Dis 1998; 178:815-819.
58. Weldon S, McNally P, McElvaney NG, Elborn JS, McAuley DF, Wartelle J, Belaaouaj A, Levine RL, Taggart CC: Decreased levels of secretory leucoprotease inhibitor in the Pseudomonas-infected cystic fibrosis lung are due to neutrophil elastase degradation. J Immunol 2009; 183:8148-8156.
59. Novak RM, Donoval BA, Graham PJ, Boksa LA, Spear G, Hershow RC, Chen HY, Landay A: Cervicovaginal levels of lactoferrin, secretory leukocyte protease inhibitor, and RANTES and the effects of coexisting vaginoses in human immunodeficiency virus (HIV)-seronegative women with a high risk of heterosexual acquisition of HIV infection. Clin Vaccine Immunol 2007; 14:1102-1107.
60. Sachdeva N, Oshima K, Cotter A, Ashman M, Davila L, Okazaki T, Inaba N, Asthana D: Analysis of immunological markers associated with pregnancy and HIV-1 infection: relevance in perinatal transmission in HIV-1-infected pregnant women with low plasma viral load. Am J Reprod Immunol 2008; 60:264-273.
61. Stock SJ, Duthie L, Tremaine T, Calder AA, Kelly RW, Riley SC: Elafin (SKALP/Trappin-2/proteinase inhibitor-3) is produced by the cervix in pregnancy and cervicovaginal levels are diminished in bacterial vaginosis. Reprod Sci 2009; 16:1125-1134.
62. Gameiro C, Romao F: Changes in the immune system during menopause and aging. Front Biosci (Elite Ed) 2010; 2:1299-1303.
63. Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G: Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda) 2008; 23:64-74.
64. Ogra PL: Ageing and its possible impact on mucosal immune responses. Ageing Res Rev 2010; 9:101-106.
65. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM: Aging of the innate immune system. Curr Opin Immunol 2010; 22:507-513.
66. Leng J, Goldstein DR: Impact of aging on viral infections. Microbes Infect 2010; 12:1120-1124.
67. Taylor LD, Daniels CK, Schmucker DL: Ageing compromises gastrointestinal mucosal immune response in the rhesus monkey. Immunology 1992; 75:614-618.
68. Summers PR: Unique skin immunology of the lower female genital tract with age. In Textbook of Aging Skin. MA Farage, KW Miller, HI Maibach (eds.). Berlin, Springer-Verlag, 2010, pp 255-257.
69. Shaw JL, Petraki C, Watson C, Bocking A, Diamandis EP: Role of tissue kallikrein-related peptidases in cervical mucus remodeling and host defense. Biol Chem 2008; 389:1513-1522.
70. Goetzl EJ, Huang MC, Kon J, Patel K, Schwartz JB, Fast K, Ferrucci L, Madara K, Taub DD, Longo DL: Gender specificity of altered human immune cytokine profiles in aging. FASEB J 2010; 24:3580-3589.
71. Mselle TF, Meadows SK, Eriksson M, Smith JM, Shen L, Wira CR, Sentman CL: Unique characteristics of NK cells throughout the human female reproductive tract. Clin Immunol 2007; 124:69-76.
72. Fahey JV, Wright JA, Shen L, Smith JM, Ghosh M, Rossoll RM, Wira CR: Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol 2008; 1:317-325.
73. Han JH, Kim MS, Lee MY, Kim TH, Lee MK, Kim HR, Myung SC: Modulation of human β-defensin-2 expression by 17β-estradiol and progesterone in vaginal epithelial cells. Cytokine 2009; 49:209-214.
74. Fahey JV, Wira CR: Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture. J Infect Dis 2002; 185:1606-1613.
75. Wahl S, McNeely T, Janoff E, Shugars D, Worley P, Tucker C, Orenstein J: Secretory leukocyte protease inhibitor (SLPI) in mucosal fluids inhibits HIV-1. Oral Dis 1997; 3(Suppl. 1):S64-S69.
76. Shimoya K, Zhang Q, Temma K, Kimura T, Tsujie T, Tsutsui T, Wasada K, Kanzaki T, Koyama M, Murata Y: Secretory leukocyte protease inhibitor levels in cervicovaginal secretion of elderly women. Maturitas 2006; 54:141-148.
77. Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, Ochiel DO: Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 2010; 63:544-565.
78. King AE, Fleming DC, Critchley HOD, Kelly RW: Differential expression of the natural antimicrobials, beta-defensins 3 and 4, in human endometrium. J Reprod Immunol 2003; 59:1-16.
79. Wira CR, Fahey JV, Sentman CL, Pioli PA, Shen L: Innate and adaptive immunity in female genital tract: cellular responses and interactions. Immunol Rev 2005; 206:306-335.
80. Mselle TF, Howell AL, Ghosh M, Wira CR, Sentman CL: Human uterine natural killer cells but not blood natural killer cells inhibit human immunodeficiency virus type 1 infection by secretion of CXCL12. J Virol 2009; 83:11188-11195.
81. Smith JM, Wira CR, Fanger MW, Shen L: Human fallopian tube neutrophils - a distinct phenotype from blood neutrophils. Am J Reprod Immunol 2006; 56:218-229.
82. Ghosh M, Fahey JV, Shen Z, Lahey T, Cu-Uvin S, Wu Z, Mayer K, Wright PF, Kappes JC, Ochsenbauer C, Wira CR: Anti-HIV activity in cervical-vaginal secretions from HIV-positive and -negative women correlate with innate antimicrobial levels and IgG antibodies. PLoS ONE 2010; 5:e11366.
83. Fahey J, Bodwell J, Hickey D, Ghosh M, Muia M, Wira CR: New approaches to making the microenvironment of the female reproductive tract hostile to HIV. Am J Reprod Immunol 2011; 65:334-343.
84. Ghosh M, Fahey J, Wira C: Differential susceptability of HIV strains to innate immune factors in human cervical-vaginal secretions. Virus Adapt Treat 2010; 2010:63-71.
85. Hazlett L, Wu M: Defensins in innate immunity. Cell Tissue Res 2011; 343:175-188.
86. Mackewicz CE, Yuan J, Tran P, Diaz L, Mack E, Selsted ME, Levy JA: alpha-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 2003; 17:F23-F32.
87. Ellison 3rd RT, Giehl TJ: Killing of gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 1991; 88:1080-1091.
88. van Wetering S, van der Linden AC, van Sterkenburg MA, de Boer WI, Kuijpers AL, Schalkwijk J, Hiemstra PS: Regulation of SLPI and elafin release from bronchial epithelial cells by neutrophil defensins. Am J Physiol Lung Cell Mol Physiol 2000; 278:L51-L58.
89. Shaw JL, Smith CR, Diamandis EP: Proteomic analysis of human cervico-vaginal fluid. J Proteome Res 2007; 6:2859-2865.
90. Monell CR, Strand M: Structural and functional similarities between synthetic HIV gp41 peptides and defensins. Clin Immunol Immunopathol 1994; 71:315-324.
91. White SH, Wimley WC, Selsted ME: Structure, function, and membrane integration of defensins. Curr Opin Struct Biol 1995; 5:521-527.
92. Wira CR, Ghosh M, Smith JM, Shen L, Connor RI, Sundstrom P, Frechette GM, Hill EM, Fahey JV: Epithelial cell secretions from the human female reproductive tract inhibit sexually transmitted pathogens and Candida albicans but not Lactobacillus. Mucosal Immunol 2010. doi: .
93. Venkataraman N, Cole AL, Svoboda P, Pohl J, Cole AM: Cationic polypeptides are required for anti-HIV-1 activity of human vaginal fluid. J Immunol 2005; 175:7560-7567.
94. Seidel A, Ye Y, de Armas LR, Soto M, Yarosh W, Marcsisin RA, Tran D, Selsted ME, Camerini D: Cyclic and acyclic defensins inhibit human immunodeficiency virus type-1 replication by different mechanisms. PLoS ONE 2010; 5:e9737.
95. Fakioglu E, Wilson SS, Mesquita PM, Hazrati E, Cheshenko N, Blaho JA, Herold BC: Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a novel immune evasion mechanism. J Virol 2008; 82:9337-9344.
96. John M, Keller MJ, Fam EH, Cheshenko N, Hogarty K, Kasowitz A, Wallenstein S, Carlucci MJ, Tuyama AC, Lu W, Klotman ME, Lehrer RI, Herold BC: Cervicovaginal secretions contribute to innate resistance to herpes simplex virus infection. J Infect Dis 2005; 192:1731-1740.
97. Jenssen H, Sandvik K, Andersen JH, Hancock RE, Gutteberg TJ: Inhibition of HSV cell-to-cell spread by lactoferrin and lactoferricin. Antiviral Res 2008; 79:192-198.
98. Hazrati E, Galen B, Lu W, Wang W, Ouyang Y, Keller MJ, Lehrer RI, Herold BC: Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection. J Immunol 2006; 177:8658-8666.
99. Buck CB, Day PM, Thompson CD, Lubkowski J, Lu W, Lowy DR, Schiller JT: Human alpha-defensins block papillomavirus infection. Proc Natl Acad Sci U S A 2006; 103:1516-1521.
100. Caberg JH, Hubert P, Herman L, Herfs M, Roncarati P, Boniver J, Delvenne P: Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20. Cancer Immunol Immunother 2009; 58:39-47.
101. Duffy CL, Phillips SL, Klingelhutz AJ: Microarray analysis identifies differentiation-associated genes regulated by human papillomavirus type 16 E6. Virology 2003; 314:196-205.
102. Kai-Larsen Y, Agerberth B: The role of the multifunctional peptide LL-37 in host defense. Front Biosci 2008; 13:3760-3767.
103. Brunham RC, Rey-Ladino J: Immunology of Chlamydia infection: implications for a Chlamydia trachomatis vaccine. Nat Rev Immunol 2005; 5:149-161.
104. CDC Fact sheet 2010.
105. Draper DL, Landers DV, Krohn MA, Hillier SL, Wiesenfeld HC, Heine RP: Levels of vaginal secretory leukocyte protease inhibitor are decreased in women with lower reproductive tract infections. Am J Obstet Gynecol 2000; 183:1243-1248.
106. Wiechula B, Cholewa K, Ekiel A, Romanik M, Dolezych H, Martirosian G: HBD-1 and hBD-2 are expressed in cervico-vaginal lavage in female genital tract due to microbial infections. Ginekol Pol 2010; 81:268-271.
107. Yasin B, Harwig SS, Lehrer RI, Wagar EA: Susceptibility of Chlamydia trachomatis to protegrins and defensins. Infect Immun 1996; 64:709-713.
108. Cederlund A, Agerberth B, Bergman P: Specificity in killing pathogens is mediated by distinct repertoires of human neutrophil peptides. J Innate Immun 2010; 2:508-521.
109. Cu-Uvin S, Hogan JW, Caliendo AM, Harwell J, Mayer KH, Carpenter CC: Association between bacterial vaginosis and expression of human immunodeficiency virus type 1 RNA in the female genital tract. Clin Infect Dis 2001; 33:894-896.
110. Hillier SL: The complexity of microbial diversity in bacterial vaginosis. N Engl J Med 2005; 353:1886-1887.
111. Balkus J, Agnew K, Lawler R, Mitchell C, Hitti J: Effects of pregnancy and bacterial vaginosis on proinflammatory cytokine and secretory leukocyte protease inhibitor concentrations in vaginal secretions. J Preg 2010 (online). doi: .
112. Sommer U, Costello CE, Hayes GR, Beach DH, Gilbert RO, Lucas JJ, Singh BN: Identification of Trichomonas vaginalis cysteine proteases that induce apoptosis in human vaginal epithelial cells. J Biol Chem 2005; 280:23853-23860.
113. Magnus M, Clark R, Myers L, Farley T, Kissinger PJ: Trichomonas vaginalis among HIV-Infected women: are immune status or protease inhibitor use associated with subsequent T. vaginalis positivity? Sex Transm Dis 2003; 30:839-843.
114. Sorvillo F, Smith L, Kerndt P, Ash L: Trichomonas vaginalis, HIV, and African-Americans. Emerg Infect Dis 2001; 7:927-932.
115. Fichorova RN, Trifonova RT, Gilbert RO, Costello CE, Hayes GR, Lucas JJ, Singh BN: Trichomonas vaginalis lipophosphoglycan triggers a selective upregulation of cytokines by human female reproductive tract epithelial cells. Infect Immun 2006; 74:5773-5779.
116. Witkin SS, Linhares IM, Giraldo P: Bacterial flora of the female genital tract: function and immune regulation. Best Pract Res Clin Obstet Gynaecol 2007; 21:347-354.
117. Ahmed N, Hayashi T, Hasegawa A, Furukawa H, Okamura N, Chida T, Masuda T, Kannagi M: Suppression of human immunodeficiency virus type 1 replication in macrophages by commensal bacteria preferentially stimulating Toll-like receptor 4. J Gen Virol 2010; 91:2804-2813.
118. King AE, Critchley HO, Kelly RW: Innate immune defences in the human endometrium. Reprod Biol Endocrinol 2003; 1:116.
119. Ochiel DO, Fahey JV, Ghosh M, Haddad SN, Wira CR: Innate immunity in the female reproductive tract: role of sex hormones in regulating uterine epithelial cell protection against pathogens. Curr Womens Health Rev 2008; 4:102-117.
120. Murthy A, Lehrer R, Harwig S, Miyasaki K: In vitro candidastatic properties of the human neutrophil calprotectin complex. J Immunol 1993; 151:6291-6301.
121. Agerberth B, Charo J, Werr J, Olsson B, Idali F, Lindbom L, Kiessling R, Jornvall H, Wigzell H, Gudmundsson GH: The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 2000; 96:3086-3093.
122. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI: Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 1985; 76:1427-1435.
123. Levinson P, Kaul R, Kimani J, Ngugi E, Moses S, MacDonald KS, Broliden K, Hirbod T; Kibera HIV Study Group: Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS 2009; 23:309-317.
124. Hein M, Valore EV, Helmig RB, Uldbjerg N, Ganz T: Antimicrobial factors in the cervical mucus plug. Am J Obstet Gynecol 2002; 187:137-144.
125. Duits LA, Ravensbergen B, Rademaker M, Hiemstra PS, Nibbering PH: Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 2002; 106:517-525.
126. Han JH, Kim MS, Lee MY, Kim TH, Lee M-K, Kim HR, Myung SC: Modulation of human [beta]-defensin-2 expression by 17[beta]-estradiol and progesterone in vaginal epithelial cells. Cytokine 2010; 49:209-214.
127. Cremel M, Berlier W, Hamzeh H, Cognasse F, Lawrence P, Genin C, Bernengo JC, Lambert C, Dieu-Nosjean MC, Delezay O: Characterization of CCL20 secretion by human epithelial vaginal cells: involvement in Langerhans cell precursor attraction. J Leukoc Biol 2005; 78:158-166.
128. Pfundt R, van Ruissen F, van Vlijmen-Willems IM, Alkemade HA, Zeeuwen PL, Jap PH, Dijkman H, Fransen J, Croes H, van Erp PE, Schalkwijk J: Constitutive and inducible expression of SKALP/elafin provides anti-elastase defense in human epithelia. J Clin Investig 1996; 98:1389-1399.
129. Narvekar N, Lakha F, Critchley HO, Glasier AF, Williams AR, Leminen R, Heikinheimo O, Kelly RW, Baird DT: Changes in vaginal morphology, steroid receptor and natural antimicrobial content following treatment with low-dose mifepristone. Contraception 2007; 75:271-280.
130. Pillay K, Coutsoudis A, Agadzi-Naqvi AK, Kuhn L, Coovadia HM, Janoff EN: Secretory leukocyte protease inhibitor in vaginal fluids and perinatal human immunodeficiency virus type 1 transmission. J Infect Dis 2001; 183:653-656.
131. Casslen B, Rosengren M, Ohlsson K: Localization and quantitation of a low molecular weight proteinase inhibitor, antileukoprotease, in the human uterus. Hoppe Seylers Z Physiol Chem 1981; 362:953-961.
132. Frohm Nilsson M, Sandstedt B, Sorensen O, Weber G, Borregaard N, Stahle-Backdahl M: The human cationic antimicrobial protein (hCAP18), a peptide antibiotic, is widely expressed in human squamous epithelia and colocalizes with interleukin-6. Infect Immun 1999; 67:2561-2566.
133. Cowland JB, Johnsen AH, Borregaard N: hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett 1995; 368:173-176.
134. Abtin A, Eckhart L, Glaser R, Gmeiner R, Mildner M, Tschachler E: The antimicrobial heterodimer S100A8/S100A9 (calprotectin) is upregulated by bacterial flagellin in human epidermal keratinocytes. J Invest Dermatol 2010; 130:2423-2430.
135. Kido J, Hayashi N, Kataoka M, Nagata T: Calprotectin expression in human monocytes: induction by porphyromonas gingivalis lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1beta. J Periodontol 2005; 76:437-442.
136. Ming L, Xiaoling P, Yan L, Lili W, Qi W, Xiyong Y, Boyao W, Ning H: Purification of antimicrobial factors from human cervical mucus. Hum Reprod 2007; 22:1810-1815.
137. Eggert-Kruse W, Botz I, Pohl S, Rohr G, Strowitzki T: Antimicrobial activity of human cervical mucus. Hum Reprod 2000; 15:778-784.
138. Lollike K, Kjeldsen L, Sengelov H, Borregaard N: Lysozyme in human neutrophils and plasma. A parameter of myelopoietic activity. Leukemia 1995; 9:159-164.
139. Cohen MS, Britigan BE, French M, Bean K: Preliminary observations on lactoferrin secretion in human vaginal mucus: variation during the menstrual cycle, evidence of hormonal regulation, and implications for infection with Neisseria gonorrhoeae. Am J Obstet Gynecol 1987; 157:1122-1125.
140. Oberley RE, Goss KL, Ault KA, Crouch EC, Snyder JM: Surfactant protein D is present in the human female reproductive tract and inhibits Chlamydia trachomatis infection. Mol Hum Reprod 2004; 10:861-870.
141. Oberley RE, Goss KL, Dahmoush L, Ault KA, Crouch EC, Snyder JM: A role for surfactant protein D in innate immunity of the human prostate. Prostate 2005; 65:241-251.
142. Oberley RE, Goss KL, Hoffmann DS, Ault KA, Neff TL, Ramsey KH, Snyder JM: Regulation of surfactant protein D in the mouse female reproductive tract in vivo. Mol Hum Reprod 2007; 13:863-868.
143. Garcia-Verdugo I, Tanfin Z, Breuiller-Fouche M: Surfactant protein A: an immunoregulatory molecule involved in female reproductive biology. Int J Biochem Cell Biol 2010; 42:1779-1783.
144. Madsen J, Tornoe I, Nielsen O, Koch C, Steinhilber W, Holmskov U: Expression and localization of lung surfactant protein A in human tissues. Am J Respir Cell Mol Biol 2003; 29:591-597.
145. MacNeill C, Umstead TM, Phelps DS, Lin Z, Floros J, Shearer DA, Weisz J: Surfactant protein A, an innate immune factor, is expressed in the vaginal mucosa and is present in vaginal lavage fluid. Immunology 2004; 111:91-99.
146. Crombie R, Silverstein RL, MacLow C, Pearce SF, Nachman RL, Laurence J: Identification of a CD36-related thrombospondin 1-binding domain in HIV-1 envelope glycoprotein gp120: relationship to HIV-1-specific inhibitory factors in human saliva. J Exp Med 1998; 187:25-35.
147. Wu MP, Tzeng CC, Wu LW, Huang KF, Chou CY: Thrombospondin-1 acts as a fence to inhibit angiogenesis that occurs during cervical carcinogenesis. Cancer J 2004; 10:27-32.
148. Moutsopoulos NM, Greenwell-Wild T, Wahl SM: Differential mucosal susceptibility in HIV-1 transmission and infection. Adv Dent Res 2006; 19:52-56.
149. Wang Z, Widgren EE, Sivashanmugam P, O'Rand MG, Richardson RT: Association of eppin with semenogelin on human spermatozoa. Biol Reprod 2005; 72:1064-1070.
150. Yenugu S, Richardson RT, Sivashanmugam P, Wang Z, O'Rand MG, French FS, Hall SH: Antimicrobial activity of human EPPIN, an androgen-regulated, sperm-bound protein with a whey acidic protein motif. Biol Reprod 2004; 71:1484-1490.
151. Zhao C, Nguyen T, Yusifov T, Glasgow BJ, Lehrer RI: Lipophilins: human peptides homologous to rat prostatein. Biochem Biophys Res Commun 1999; 256:147-155.
152. Seppala M, Taylor RN, Koistinen H, Koistinen R, Milgrom E: Glycodelin: a major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. Endocr Rev 2002; 23:401-430.
153. Fluckinger M, Haas H, Merschak P, Glasgow BJ, Redl B: Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores. Antimicrob Agents Chemother 2004; 48:3367-3372.
154. Halttunen M, Kamarainen M, Koistinen H: Glycodelin: a reproduction-related lipocalin. Biochim Biophys Acta 2000; 1482:149-156.
155. Jacobsen F, Baraniskin A, Mertens J, Mittler D, Mohammadi-Tabrisi A, Schubert S, Soltau M, Lehnhardt M, Behnke B, Gatermann S, Steinau HU, Steinstraesser L: Activity of histone H1.2 in infected burn wounds. J Antimicrob Chemother 2005; 55:735-741.
156. Kawasaki H, Iwamuro S: Potential roles of histones in host defense as antimicrobial agents. Infect Disord Drug Targets 2008; 8:195-205.
157. Tollin M, Bergman P, Svenberg T, Jornvall H, Gudmundsson GH, Agerberth B: Antimicrobial peptides in the first line defence of human colon mucosa. Peptides 2003; 24:523-530.
158. Denison F, Kelly R, Calder A, Riley S: Secretory leukocyte protease inhibitor concentration increases in amniotic fluid with the onset of labour in women: characterization of sites of release within the uterus. J Endocrinol 1999; 161:299-306.