Advertisement

Sex and sex steroids impact influenza pathogenesis across the life course

  • Landon G. vom Steeg
  • Sabra L. Klein
Review

Abstract

Males and females differ in the outcome of influenza A virus (IAV) infections, which depends significantly on age. During a typical seasonal influenza epidemic, young children (< 10 years of age) and aged adults (65+ years of age) are at greatest risk for severe disease, and among these age groups, males tend to suffer a worse outcome from IAV infection than females. Following infection with either pandemic or outbreak strains of IAVs, females of reproductive ages (i.e., 15–49 years of age) experience a worse outcome than their male counterparts. Among females of reproductive ages, pregnancy is one factor linked to an increased risk of severe outcome of influenza, although it is not the sole factor explaining the female-preponderance of severe disease. Small animal models of influenza virus infection illustrate that inflammatory immune responses and repair of damaged tissue following IAV infection also differ between the sexes and impact the outcome of infection. There also is growing evidence that sex steroid hormones, including estrogens, progesterone, and testosterone, directly impact immune responses during IAV infection to alter outcomes. Greater consideration of the combined effects of sex and age as biological variables in epidemiological, clinical, and animal studies of influenza pathogenesis is needed.

Keywords

Estrogen Gender Immunopathology Pandemic Progesterone Testosterone 

Notes

Acknowledgements

The writing of this review was supported by the NIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N272201400007C (SLK).

References

  1. 1.
    vom Steeg LG, Klein SL (2016) SeXX matters in infectious disease pathogenesis. PLoS Pathog 12:e1005374CrossRefGoogle Scholar
  2. 2.
    Klein SL, Pekosz A, Passaretti C, Anker M, Olukoya P (2010) Sex, gender and influenza. World Health Organization, GenevaGoogle Scholar
  3. 3.
    Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16:626–638CrossRefGoogle Scholar
  4. 4.
    Flanagan KL, Fink AL, Plebanski M, Klein SL (2017) Sex and gender differences in the outcomes of vaccination over the life course. Annu Rev Cell Dev Biol 33:577–599CrossRefGoogle Scholar
  5. 5.
    Peiris JS, Hui KP, Yen HL (2010) Host response to influenza virus: protection versus immunopathology. Curr Opin Immunol 22:475–481CrossRefGoogle Scholar
  6. 6.
    Cloutier A, Marois I, Cloutier D, Verreault C, Cantin AM, Richter MV (2012) The prostanoid 15-deoxy-Delta12,14-prostaglandin-j2 reduces lung inflammation and protects mice against lethal influenza infection. J Infect Dis 205:621–630CrossRefGoogle Scholar
  7. 7.
    Walsh KB, Teijaro JR, Wilker PR, Jatzek A, Fremgen DM, Das SC, Watanabe T, Hatta M, Shinya K, Suresh M, Kawaoka Y, Rosen H, Oldstone MB (2011) Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci U S A 108:12018–12023CrossRefGoogle Scholar
  8. 8.
    Chitnis AS, Truelove SA, Drunkenmiller JK, Hefferman RT, Davis JP (2010) Epidemiologic and clinical features among patients hospitalized in Wisconsin with 2009 H1N1 influenza A virus infections, April to August 2009. Wis Med J 109:201–209Google Scholar
  9. 9.
    Yasui H, Kiyoshima J, Hori T (2004) Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus casei Shirota. Clin Diagn Lab Immunol 11:675–679PubMedPubMedCentralGoogle Scholar
  10. 10.
    Sun S, Zhao G, Xia W, Hu J, Guo Y, Wu X, Tan Y, Zhou Y (2011) Age-related sensitivity and pathological differences in infection by 2009 pandemic influenza A (H1N1) virus. Virol J 8:52CrossRefGoogle Scholar
  11. 11.
    Huang SS, Banner D, Degousee N, Leon AJ, Xu L, Paquette SG, Kanagasabai T, Fang Y, Rubino S, Rubin B, Kelvin DJ, Kelvin AA (2012) Differential pathological and immune responses in newly weaned ferrets are associated with a mild clinical outcome of pandemic 2009 H1N1 infection. J Virol 86:13187–13201CrossRefGoogle Scholar
  12. 12.
    Bouvier NM, Lowen AC (2010) Animal models for influenza virus pathogenesis and transmission. Viruses 2:1530–1563CrossRefGoogle Scholar
  13. 13.
    Quach C, Piche-Walker L, Platt R, Moore D (2003) Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy. Pediatrics 112:e197–e201CrossRefGoogle Scholar
  14. 14.
    Crighton EJ, Moineddin R, Mamdani M, Upshur RE (2004) Influenza and pneumonia hospitalizations in Ontario: a time-series analysis. Epidemiol Infect 132:1167–1174CrossRefGoogle Scholar
  15. 15.
    Crighton EJ, Elliott SJ, Kanaroglou P, Moineddin R, Upshur RE (2008) Spatio-temporal analysis of pneumonia and influenza hospitalizations in Ontario, Canada. Geospat Health 2:191–202CrossRefGoogle Scholar
  16. 16.
    Jensen-Fangel S, Mohey R, Johnsen SP, Andersen PL, Sorensen HT, Ostergaard L (2004) Gender differences in hospitalization rates for respiratory tract infections in Danish youth. Scand J Infect Dis 36:31–36CrossRefGoogle Scholar
  17. 17.
    Noymer A, Garenne M (2000) The 1918 influenza epidemic’s effects on sex differentials in mortality in the United States. Popul Dev Rev 26:565–581CrossRefGoogle Scholar
  18. 18.
    Nhamoyebonde S, Leslie A (2014) Biological differences between the sexes and susceptibility to tuberculosis. J Infect Dis 209(Suppl 3):S100–S106CrossRefGoogle Scholar
  19. 19.
    Noymer A (2009) Testing the influenza-tuberculosis selective mortality hypothesis with Union Army data. Soc Sci Med 68:1599–1608CrossRefGoogle Scholar
  20. 20.
    Serfling RE, Sherman IL, Houseworth WJ (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 86:433–441CrossRefGoogle Scholar
  21. 21.
    Kilbourne ED (2006) Influenza pandemics of the 20th century. Emerg Infect Dis 12:9–14CrossRefGoogle Scholar
  22. 22.
    Jacobs JH, Archer BN, Baker MG, Cowling BJ, Heffernan RT, Mercer G, Uez O, Hanshaoworakul W, Viboud C, Schwartz J, Tchetgen Tchetgen E, Lipsitch M (2012) Searching for sharp drops in the incidence of pandemic A/H1N1 influenza by single year of age. PLoS One 7:e42328CrossRefGoogle Scholar
  23. 23.
    Eshima N, Tokumaru O, Hara S, Bacal K, Korematsu S, Tabata M, Karukaya S, Yasui Y, Okabe N, Matsuishi T (2011) Sex- and age-related differences in morbidity rates of 2009 pandemic influenza A H1N1 virus of swine origin in Japan. PLoS One 6:e19409CrossRefGoogle Scholar
  24. 24.
    Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, Stelfox T, Bagshaw S, Choong K, Lamontagne F, Turgeon AF, Lapinsky S, Ahern SP, Smith O, Siddiqui F, Jouvet P, Khwaja K, McIntyre L, Menon K, Hutchison J, Hornstein D, Joffe A, Lauzier F, Singh J, Karachi T, Wiebe K, Olafson K, Ramsey C, Sharma S, Dodek P, Meade M, Hall R, Fowler RA (2009) Critically ill patients with 2009 influenza A (H1N1) infection in Canada. Jama 302:1872–1879CrossRefGoogle Scholar
  25. 25.
    Townsend EA, Miller VM, Prakash YS (2012) Sex differences and sex steroids in lung health and disease. Endocr Rev 33:1–47CrossRefGoogle Scholar
  26. 26.
    WHO (2013) Update on human cases of influenza at the human-animal interface, 2012. Wkly Epidemiol Rec. 88(13):137–44Google Scholar
  27. 27.
    Hoffmann J, Otte A, Thiele S, Lotter H, Shu Y, Gabriel G (2015) Sex differences in H7N9 influenza A virus pathogenesis. Vaccine 33:6949–6954CrossRefGoogle Scholar
  28. 28.
    Robinson DP, Lorenzo ME, Jian W, Klein SL (2011) Elevated 17beta-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog 7:e1002149CrossRefGoogle Scholar
  29. 29.
    Robinson DP, Huber SA, Moussawi M, Roberts B, Teuscher C, Watkins R, Arnold AP, Klein SL (2011) Sex chromosome complement contributes to sex differences in Coxsackievirus B3 but not influenza A virus pathogenesis. Biol Sex Differ 2:8CrossRefGoogle Scholar
  30. 30.
    Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL (2014) 17beta-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. J Virol 88:4711–4720CrossRefGoogle Scholar
  31. 31.
    Hall OJ, Limjunyawong N, Vermillion MS, Robinson DP, Wohlgemuth N, Pekosz A, Mitzner W, Klein SL (2016) Progesterone-based therapy protects against influenza by promoting lung repair and recovery in females. PLoS Pathog 12:e1005840CrossRefGoogle Scholar
  32. 32.
    vom Steeg LG, Vermillion MS, Hall OJ, Alam O, McFarland R, Chen H, Zirkin B, Klein SL (2016) Age and testosterone mediate influenza pathogenesis in male mice. Am J Physiol Lung Cell Mol Physiol 311:L1234–L1L44CrossRefGoogle Scholar
  33. 33.
    Celestino I, Checconi P, Amatore D, De Angelis M, Coluccio P, Dattilo R, Alunni Fegatelli D, Clemente AM, Matarrese P, Torcia MG, Mancinelli R, Mammola CL, Garaci E, Vestri AR, Malorni W, Palamara AT, Nencioni L (2018) Differential redox state contributes to sex disparities in the response to influenza virus infection in male and female mice. Front Immunol 9:1747CrossRefGoogle Scholar
  34. 34.
    Lorenzo ME, Hodgson A, Robinson DP, Kaplan JB, Pekosz A, Klein SL (2011) Antibody responses and cross protection against lethal influenza A viruses differ between the sexes in C57BL/6 mice. Vaccine 29:9246–9255CrossRefGoogle Scholar
  35. 35.
    Larcombe AN, Foong RE, Bozanich EM, Berry LJ, Garratt LW, Gualano RC, Jones JE, Dousha LF, Zosky GR, Sly PD (2011) Sexual dimorphism in lung function responses to acute influenza A infection. Influenza Other Respir Viruses 5:334–342CrossRefGoogle Scholar
  36. 36.
    Vermillion MS, Ursin RL, Kuok DIT, vom Steeg LG, Wohlgemuth N, Hall OJ, Fink AL, Sasse E, Nelson A, Ndeh R, McGrath-Morrow S, Mitzner W, Chan MCW, Pekosz A, Klein SL (2018) Production of amphiregulin and recovery from influenza is greater in males than females. Biol Sex Differ 9:24CrossRefGoogle Scholar
  37. 37.
    Sun J, Madan R, Karp CL, Braciale TJ (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15:277–284CrossRefGoogle Scholar
  38. 38.
    Tate MD, Schilter HC, Brooks AG, Reading PC (2011) Responses of mouse airway epithelial cells and alveolar macrophages to virulent and avirulent strains of influenza A virus. Viral Immunol 24:77–88CrossRefGoogle Scholar
  39. 39.
    Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, Angelosanto JM, Laidlaw BJ, Yang CY, Sathaliyawala T, Kubota M, Turner D, Diamond JM, Goldrath AW, Farber DL, Collman RG, Wherry EJ, Artis D (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12:1045–1054CrossRefGoogle Scholar
  40. 40.
    Vermillion MS, Ursin RL, Attreed SE, Klein SL (2018) Estriol reduces pulmonary immune cell recruitment and inflammation to protect female mice from severe influenza. Endocrinology 159:3306–3320CrossRefGoogle Scholar
  41. 41.
    Wang CS, Wang ST, Chou P (2002) Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community. Vaccine 20:2494–2499CrossRefGoogle Scholar
  42. 42.
    WHO (2014) WHO risk assessment of human infection with avian influenza A (H7N9) virus, World Health Organization Website (http://www.who.int/influenza/human_animal_interface/influenza_h7n9/Risk_Assessment/en/). Accessed 3 Aug 2018
  43. 43.
    Skowronski DM, Janjua NZ, Kwindt TL, De Serres G (2013) Virus-host interactions and the unusual age and sex distribution of human cases of influenza A (H7N9) in China, April 2013. Euro Surveill 18:20465CrossRefGoogle Scholar
  44. 44.
    Wang C, Yu H, Horby PW, Cao B, Wu P, Yang S, Gao H, Li H, Tsang TK, Liao Q, Gao Z, Ip DK, Jia H, Jiang H, Liu B, Ni MY, Dai X, Liu F, Van Kinh N, Liem NT, Hien TT, Li Y, Yang J, Wu JT, Zheng Y, Leung GM, Farrar JJ, Cowling BJ, Uyeki TM, Li L (2014) Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. Clin Infect Dis 58(8):1095–10CrossRefGoogle Scholar
  45. 45.
    Li Q, Zhou L, Zhou M, Chen Z, Li F, Wu H, Xiang N, Chen E, Tang F, Wang D, Meng L, Hong Z, Tu W, Cao Y, Li L, Ding F, Liu B, Wang M, Xie R, Gao R, Li X, Bai T, Zou S, He J, Hu J, Xu Y, Chai C, Wang S, Gao Y, Jin L, Zhang Y, Luo H, Yu H, He J, Li Q, Wang X, Gao L, Pang X, Liu G, Yan Y, Yuan H, Shu Y, Yang W, Wang Y, Wu F, Uyeki TM, Feng Z (2014) Epidemiology of human infections with avian influenza A (H7N9) virus in China. N Engl J Med 370:520–532CrossRefGoogle Scholar
  46. 46.
    Dudley JP, Mackay IM (2013) Age-specific and sex-specific morbidity and mortality from avian influenza A (H7N9). J Clin Virol 58:568–570CrossRefGoogle Scholar
  47. 47.
    Cowling BJ, Jin L, Lau EH, Liao Q, Wu P, Jiang H, Tsang TK, Zheng J, Fang VJ, Chang Z, Ni MY, Zhang Q, Ip DK, Yu J, Li Y, Wang L, Tu W, Meng L, Wu JT, Luo H, Li Q, Shu Y, Li Z, Feng Z, Yang W, Wang Y, Leung GM, Yu H (2013) Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. Lancet 382:129–137CrossRefGoogle Scholar
  48. 48.
    Arima Y, Vong S (2013) Human infections with avian influenza A (H7N9) virus in China: preliminary assessments of the age and sex distribution. Western Pac Surveill Response J 4:1–3CrossRefGoogle Scholar
  49. 49.
    Yager EJ, Ahmed M, Lanzer K, Randall TD, Woodland DL, Blackman MA (2008) Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 205:711–723CrossRefGoogle Scholar
  50. 50.
    Gil A, Yassai MB, Naumov YN, Selin LK (2015) Narrowing of human influenza A virus-specific T cell receptor alpha and beta repertoires with increasing age. J Virol 89:4102–4116CrossRefGoogle Scholar
  51. 51.
    Jiang J, Bennett AJ, Fisher E, Williams-Bey Y, Shen H, Murasko DM (2009) Limited expansion of virus-specific CD8 T cells in the aged environment. Mech Ageing Dev 130:713–721CrossRefGoogle Scholar
  52. 52.
    Jiang J, Fisher EM, Murasko DM (2011) CD8 T cell responses to influenza virus infection in aged mice. Ageing Res Rev 10:422–427PubMedPubMedCentralGoogle Scholar
  53. 53.
    Parzych EM, DiMenna LJ, Latimer BP, Small JC, Kannan S, Manson B, Lasaro MO, Wherry EJ, Ertl HC (2013) Influenza virus specific CD8(+) T cells exacerbate infection following high dose influenza challenge of aged mice. Biomed Res Int 2013:876314CrossRefGoogle Scholar
  54. 54.
    Nguyen DC, Masseoud F, Lu X, Scinicariello F, Sambhara S, Attanasio R (2011) 17beta-Estradiol restores antibody responses to an influenza vaccine in a postmenopausal mouse model. Vaccine 29:2515–2518CrossRefGoogle Scholar
  55. 55.
    Pazos MA, Kraus TA, Munoz-Fontela C, Moran TM (2012) Estrogen mediates innate and adaptive immune alterations to influenza infection in pregnant mice. PLoS One 7:e40502CrossRefGoogle Scholar
  56. 56.
    Tate MD, Brooks AG, Reading PC, Mintern JD (2012) Neutrophils sustain effective CD8(+) T-cell responses in the respiratory tract following influenza infection. Immunol Cell Biol 90:197–205CrossRefGoogle Scholar
  57. 57.
    Tate MD, Deng YM, Jones JE, Anderson GP, Brooks AG, Reading PC (2009) Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol 183:7441–7450CrossRefGoogle Scholar
  58. 58.
    Hall OJ, Nachbagauer R, Vermillion MS, Fink AL, Phuong V, Hirsh A, Krammer F, Klein SL (2017) Progesterone-based contraceptives reduce adaptive immune responses and protection against heterosubtypic infection with influenza A viruses. J Virol 91(8):e02160-16.  https://doi.org/10.1128/JVI.02160-16
  59. 59.
    Davis SM, Sweet LM, Oppenheimer KH, Suratt BT, Phillippe M (2017) Estradiol and progesterone influence on influenza infection and immune response in a mouse model. Am J Reprod Immunol 78:e12695CrossRefGoogle Scholar
  60. 60.
    Trigunaite A, Dimo J, Jorgensen TN (2015) Suppressive effects of androgens on the immune system. Cell Immunol 294:87–94CrossRefGoogle Scholar
  61. 61.
    Gubbels Bupp MR, Jorgensen TN (2018) Androgen-induced immunosuppression. Front Immunol 9:794CrossRefGoogle Scholar
  62. 62.
    Zirkin BR, Tenover JL (2012) Aging and declining testosterone: past, present, and hopes for the future. J Androl 33:1111–1118CrossRefGoogle Scholar
  63. 63.
    Krause W (2006) Androgens in the demography of male life course - a review. Biodemography Soc Biol 53:4–12CrossRefGoogle Scholar
  64. 64.
    Handelsman DJ, Sikaris K, Ly LP (2016) Estimating age-specific trends in circulating testosterone and sex hormone-binding globulin in males and females across the lifespan. Ann Clin Biochem 53:377–384CrossRefGoogle Scholar
  65. 65.
    Kadel S, Kovats S (2018) Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection. Front Immunol 9:1653.  https://doi.org/10.3389/fimmu.2018.01653

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Microbiology and ImmunologyThe Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA

Personalised recommendations