Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

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Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.

Vyšlo v časopise: Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses. PLoS Pathog 7(7): e32767. doi:10.1371/journal.ppat.1002149
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002149

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1. KleinSLHuberS 2010 Sex differences in susceptibility to viral infection. KleinSLRobertsCW Sex hormones and immunity to infection Berlin Springer-Verlag 93 122

2. TheilerRNRasmussenSATreadwellTAJamiesonDJ 2008 Emerging and zoonotic infections in women. Infect Dis Clin North Am 22 755 772, vii–viii

3. FishEN 2008 The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8 737 744

4. MarriottIHuet-HudsonYM 2006 Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res 34 177 192

5. MeierAChangJJChanESPollardRBSidhuHK 2009 Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 15 955 959

6. VillacresMCLongmateJAugeCDiamondDJ 2004 Predominant type 1 CMV-specific memory T-helper response in humans: evidence for gender differences in cytokine secretion. Hum Immunol 65 476 485

7. HewagamaAPatelDYarlagaddaSStricklandFMRichardsonBC 2009 Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 10 509 516

8. CookIF 2008 Sexual dimorphism of humoral immunity with human vaccines. Vaccine 26 3551 3555

9. RobertsCWWalkerWAlexanderJ 2001 Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 14 476 488

10. AhmedSAKarpuzogluEKhanD 2010 Effects of sex steroids on innate and adaptive immunity. KleinSLRobertsCW Sex hormones and immunity to infection Berlin Springer-Verlag 19 52

11. GilliverSC 2010 Sex steroids as inflammatory regulators. J Steroid Biochem Mol Biol 120 105 115

12. KovatsSCarrerasEAgrawalH 2010 Sex steroid receptors in immune cells. KleinSLRobertsCW Sex hormones and immunity to infection Berlin Springer-Verlag 53 92

13. D'AgostinoPMilanoSBarberaCDi BellaGLa RosaM 1999 Sex hormones modulate inflammatory mediators produced by macrophages. Ann N Y Acad Sci 876 426 429

14. RettewJAHuet-HudsonYMMarriottI 2008 Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod 78 432 437

15. StraubRH 2007 The complex role of estrogens in inflammation. Endocr Rev 28 521 574

16. GiraudSNCaronCMPham-DinhDKitabgiPNicotAB 2010 Estradiol inhibits ongoing autoimmune neuroinflammation and NFkappaB-dependent CCL2 expression in reactive astrocytes. Proc Natl Acad Sci U S A 107 8416 8421

17. WiraCRFaheyJVGhoshMPatelMVHickeyDK 2010 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 63 544 565

18. SpeyerCLRancilioNJMcClintockSDCrawfordJDGaoH 2005 Regulatory effects of estrogen on acute lung inflammation in mice. Am J Physiol Cell Physiol 288 C881 890

19. ChotirmallSHGreeneCMOglesbyIKThomasWO'NeillSJ 2010 17Beta-estradiol inhibits IL-8 in cystic fibrosis by up-regulating secretory leucoprotease inhibitor. Am J Respir Crit Care Med 182 62 72

20. BiswasDKSinghSShiQPardeeABIglehartJD 2005 Crossroads of estrogen receptor and NF-kappaB signaling. Sci STKE 2005 pe27 pe27

21. KleinSLPekoszAPassarettiCAnkerMOlukoyaP 2010 Sex, gender and influenza. Geneva World Health Organization 1 58

22. SerflingREShermanILHouseworthWJ 1967 Excess pneumonia-influenza mortality by age and sex in three major influenza A2 epidemics, United States, 1957-58, 1960 and 1963. Am J Epidemiol 86 433 441

23. WHO 2008 Update: WHO-confirmed human cases of avian influenza A (H5N1) infection, November 2003-May 2008. Wkly Epidemiol Rec 83 415 420

24. KumarAZarychanskiRPintoRCookDJMarshallJ 2009 Critically ill patients with 2009 influenza A(H1N1) infection in Canada. Jama 302 1872 1879

25. CampbellARodinRKroppRMaoYHongZ 2010 Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza. CMAJ 182 349 355

26. FieldingJHigginsNGregoryJGrantKCattonM 2009 Pandemic H1N1 influenza surveillance in Victoria, Australia, April - September, 2009. Euro Surveill 14 pii:19368

27. OliveiraWCarmoEPennaGKuchenbeckerRSantosH 2009 Pandemic H1N1 influenza in Brazil: analysis of the first 34,506 notified cases of influenza-like illness with severe acute respiratory infection (SARI). Euro Surveill 14 pii:19362

28. DenholmJTGordonCLJohnsonPDHewagamaSSStuartRL 2010 Hospitalised adult patients with pandemic (H1N1) 2009 influenza in Melbourne, Australia. Med J Aust 192 84 86

29. GuanYPoonLLCheungCYEllisTMLimW 2004 H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci U S A 101 8156 8161

30. SzretterKJGangappaSLuXSmithCShiehWJ 2007 Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol 81 2736 2744

31. KobasaDJonesSMShinyaKKashJCCoppsJ 2007 Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445 319 323

32. KashJCTumpeyTMProllSCCarterVPerwitasariO 2006 Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443 578 581

33. de JongMDSimmonsCPThanhTTHienVMSmithGJ 2006 Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12 1203 1207

34. TumpeyTMLuXMorkenTZakiSRKatzJM 2000 Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans. J Virol 74 6105 6116

35. BuchweitzJPHarkemaJRKaminskiNE 2007 Time-dependent airway epithelial and inflammatory cell responses induced by influenza virus A/PR/8/34 in C57BL/6 mice. Toxicol Pathol 35 424 435

36. XuTQiaoJZhaoLWangGHeG 2006 Acute respiratory distress syndrome induced by avian influenza A (H5N1) virus in mice. Am J Respir Crit Care Med 174 1011 1017

37. GrinspoonS 2005 Androgen deficiency and HIV infection. Clin Infect Dis 41 1804 1805

38. DantzerRO'ConnorJCFreundGGJohnsonRWKelleyKW 2008 From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9 46 56

39. AvitsurRYirmiyaR 1999 The immunobiology of sexual behavior: gender differences in the suppression of sexual activity during illness. Pharmacol Biochem Behav 64 787 796

40. BeckerJBArnoldAPBerkleyKJBlausteinJDEckelLA 2005 Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146 1650 1673

41. MoraniAWarnerMGustafssonJA 2008 Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. J Intern Med 264 128 142

42. LarcombeANFoongREBozanichEMBerryLJGarrattLW 2011 Sexual dimorphism in lung function responses to acute influenza A infection. Influenza and Other Respiratory Viruses DOI:10.1111/j.1750-2659.2011.00236.x

43. LinKLSuzukiYNakanoHRamsburgEGunnMD 2008 CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol 180 2562 2572

44. ArnoldAP 2009 The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav 55 570 578

45. JanssonLOlssonTHolmdahlR 1994 Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J Neuroimmunol 53 203 207

46. KimSLivaSMDalalMAVerityMAVoskuhlRR 1999 Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 52 1230 1238

47. CvoroATatomerDTeeMKZogovicTHarrisHA 2008 Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol 180 630 636

48. ChadwickCCChippariSMatelanEBorges-MarcucciLEckertAM 2005 Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity. Proc Natl Acad Sci U S A 102 2543 2548

49. MainesTRJayaramanABelserJAWadfordDAPappasC 2009 Transmission and Pathogenesis of Swine-Origin 2009 A(H1N1) Influenza Viruses in Ferrets and Mice. Science 325 484 487

50. BelserJAWadfordDAPappasCGustinKMMainesTR 2010 Pathogenesis of pandemic influenza A (H1N1) and triple-reassortant swine influenza A (H1) viruses in mice. J Virol 84 4194 4203

51. WardAC 1997 Virulence of influenza A virus for mouse lung. Virus Genes 14 187 194

52. TulchinskyDHobelCJYeagerEMarshallJR 1972 Plama estradiol, estriol, and progesterone in human pregnancy. II. Clinical applications in Rh-isoimmunization disease. Am J Obstet Gynecol 113 766 770

53. Szekeres-BarthoJPolgarB 2010 Progesterone, Pregnancy, and Innate Immunity. KleinSLaRCW Sex Hormones and Immunity to Infection Berlin Springer-Verlag 205 226

54. CernetichAGarverLSJedlickaAEKleinPWKumarN 2006 Involvement of gonadal steroids and gamma interferon in sex differences in response to blood-stage malaria infection. Infect Immun 74 3190 3203

55. KleinSLBirdBHGlassGE 2000 Sex differences in Seoul virus infection are not related to adult sex steroid concentrations in Norway rats. J Virol 74 8213 8217

56. SiracusaMCOverstreetMGHousseauFScottALKleinSL 2008 17{beta}-Estradiol Alters the Activity of Conventional and IFN-Producing Killer Dendritic Cells. J Immunol 180 1423 1431

57. HuberSA 2008 Coxsackievirus B3-induced myocarditis: infection of females during the estrus phase of the ovarian cycle leads to activation of T regulatory cells. Virology 378 292 298

58. CohenPEZhuLNishimuraKPollardJW 2002 Colony-stimulating factor 1 regulation of neuroendocrine pathways that control gonadal function in mice. Endocrinology 143 1413 1422

59. Tiwari-WoodruffSMoralesLBLeeRVoskuhlRR 2007 Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A 104 14813 14818

60. McCownMFPekoszA 2005 The influenza A virus M2 cytoplasmic tail is required for infectious virus production and efficient genome packaging. J Virol 79 3595 3605