Seminars in Immunopathology

, Volume 41, Issue 2, pp 225–237 | Cite as

Sex differences in tuberculosis

  • David Hertz
  • Bianca SchneiderEmail author


Tuberculosis is the most prevalent bacterial infectious disease in humans and the leading cause of death from a single infectious agent, ranking above HIV/AIDS. The causative agent, Mycobacterium tuberculosis, is carried by an estimated two billion people globally and claims more than 1.5 million lives each year. Tuberculosis rates are significantly higher in men than in women, reflected by a male-to-female ratio for worldwide case notifications of 1.7. This phenomenon is not new and has been reported in various countries and settings over the last century. However, the reasons for the observed gender bias are not clear, potentially highly complex and discussed controversially in the literature. Both gender- (referring to sociocultural roles and behavior) and sex-related factors (referring to biological aspects) likely contribute to higher tuberculosis rates in men and will be discussed.


Tuberculosis Sex differences Male bias Inflammation Mouse models Susceptibility 



We thank Jochen Behrends and Ulrich Schaible for critical discussions and helpful comments on the manuscript.


  1. 1.
    WHO (2017) Global tuberculosis report 2017. World Health Organization, Geneva.Google Scholar
  2. 2.
    Holmes CB, Hausler H, Nunn P (1998) A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 2:96–104PubMedGoogle Scholar
  3. 3.
    Thorson A, Hoa NP, Long NH, Allebeck P, Diwan VK (2004) Do women with tuberculosis have a lower likelihood of getting diagnosed? Prevalence and case detection of sputum smear positive pulmonary TB, a population-based study from Vietnam. J Clin Epidemiol 57:398–402CrossRefPubMedGoogle Scholar
  4. 4.
    Khan MS, Dar O, Sismanidis C, Shah K, Godfrey-Faussett P (2007) Improvement of tuberculosis case detection and reduction of discrepancies between men and women by simple sputum-submission instructions: a pragmatic randomised controlled trial. Lancet 369:1955–1960CrossRefPubMedGoogle Scholar
  5. 5.
    Long NH, Johansson E, Lonnroth K, Eriksson B, Winkvist A, Diwan VK (1999) Longer delays in tuberculosis diagnosis among women in Vietnam. Int J Tuberc Lung Dis 3:388–393PubMedGoogle Scholar
  6. 6.
    Borgdorff MW, Nagelkerke NJ, Dye C, Nunn P (2000) Gender and tuberculosis: a comparison of prevalence surveys with notification data to explore sex differences in case detection. Int J Tuberc Lung Dis 4:123–132PubMedGoogle Scholar
  7. 7.
    Horton KC, MacPherson P, Houben RM, White RG, Corbett EL (2016) Sex differences in tuberculosis burden and notifications in low- and middle-income countries: a systematic review and meta-analysis. PLoS Med 13:e1002119CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hoa NB, Sy DN, Nhung NV, Tiemersma EW, Borgdorff MW, Cobelens FG (2010) National survey of tuberculosis prevalence in Viet Nam. Bull World Health Organ 88:273–280CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Centers for Disease Control and Prevention (CDC) (2017) Reported tuberculosis in the United States, 2016. US Department of Health and Human Services, Atlanta, GAGoogle Scholar
  10. 10.
    Bericht zur Epidemiologie der Tuberkulose in Deutschland für 2016.
  11. 11.
    Kizza FN, List J, Nkwata AK, Okwera A, Ezeamama AE, Whalen CC, Sekandi JN (2015) Prevalence of latent tuberculosis infection and associated risk factors in an urban African setting. BMC Infect Dis 15:165CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chen C, Zhu T, Wang Z, Peng H, Kong W, Zhou Y, Shao Y, Zhu L, Lu W (2015) High latent TB infection rate and associated risk factors in the eastern China of low TB incidence. PLoS One 10:e0141511CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Teklu T, Legesse M, Medhin G, Zewude A, Chanyalew M, Zewdie M, Wondale B, Haile-Mariam M, Pieper R, Ameni G (2018) Latent tuberculosis infection and associated risk indicators in pastoral communities in southern Ethiopia: a community based cross-sectional study. BMC Public Health 18:266CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ting WY, Huang SF, Lee MC, Lin YY, Lee YC, Feng JY, Su WJ (2014) Gender disparities in latent tuberculosis infection in high-risk individuals: a cross-sectional study. PLoS One 9:e110104CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Legesse M, Ameni G, Mamo G, Medhin G, Bjune G, Abebe F (2011) Community-based cross-sectional survey of latent tuberculosis infection in Afar pastoralists, Ethiopia, using QuantiFERON-TB Gold In-Tube and tuberculin skin test. BMC Infect Dis 11:89CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Herzmann C, Sotgiu G, Bellinger O, Diel R, Gerdes S, Goetsch U, Heykes-Uden H, Schaberg T, Lange C, consortium TBonT (2016) Risk for latent and active tuberculosis in Germany. Infection.
  17. 17.
    Ghassemieh BJ, Attia EF, Koelle DM, Mancuso JD, Narita M, Horne DJ (2016) Latent tuberculosis infection test agreement in the National Health and Nutrition Examination Survey. Am J Respir Crit Care Med 194:493–500CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nhamoyebonde S, Leslie A (2014) Biological differences between the sexes and susceptibility to tuberculosis. J Infect Dis 209(Suppl 3):S100–S106CrossRefPubMedGoogle Scholar
  19. 19.
    Rees D, Murray J (2007) Silica, silicosis and tuberculosis. Int J Tuberc Lung Dis 11:474–484PubMedGoogle Scholar
  20. 20.
    Narasimhan P, Wood J, Macintyre CR, Mathai D (2013) Risk factors for tuberculosis. Pulm Med 2013:828939CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Watkins RE, Plant AJ (2006) Does smoking explain sex differences in the global tuberculosis epidemic? Epidemiol Infect 134:333–339CrossRefPubMedGoogle Scholar
  22. 22.
    Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR (2007) Risk of tuberculosis from exposure to tobacco smoke: a systematic review and meta-analysis. Arch Intern Med 167:335–342CrossRefPubMedGoogle Scholar
  23. 23.
    Maurya V, Vijayan VK, Shah A (2002) Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis 6:942–951PubMedGoogle Scholar
  24. 24.
    Wilsnack RW, Wilsnack SC, Kristjanson AF, Vogeltanz-Holm ND, Gmel G (2009) Gender and alcohol consumption: patterns from the multinational GENACIS project. Addiction 104:1487–1500CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Development PCfHRa (2016) National tuberculosis prevalence survey 2016 PhilippinesGoogle Scholar
  26. 26.
    WHO (2016) Tuberculosis in women. Accessed 28 May 2018
  27. 27.
    Mathad JS, Gupta A (2012) Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect Dis 55:1532–1549CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Loto OM, Awowole I (2012) Tuberculosis in pregnancy: a review. J Pregnancy 2012:379271CrossRefPubMedGoogle Scholar
  29. 29.
    Klein S, Roberts C, Editors (2015) Sex and gender differences in infection and treatments for infectious diseases. Springer, VerlagCrossRefGoogle Scholar
  30. 30.
    McClelland EE, Smith JM (2011) Gender specific differences in the immune response to infection. Arch Immunol Ther Exp 59:203–213CrossRefGoogle Scholar
  31. 31.
    Pawlowski A, Jansson M, Skold M, Rottenberg ME, Kallenius G (2012) Tuberculosis and HIV co-infection. PLoS Pathog 8:e1002464CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Addo MM, Altfeld M (2014) Sex-based differences in HIV type 1 pathogenesis. J Infect Dis 209(Suppl 3):S86–S92CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kanabus A (2017) Information about tuberculosis GHE, 2017.
  34. 34.
    Janet F (2010) Tackling TB and HIV in Women: An Urgent Agenda. Accessed 29 May 2018
  35. 35.
    WHO (2009) WHO information on tuberculosis and pandemic influenza A (H1N1). Accessed 30 January 2015
  36. 36.
    Noymer A (2011) The 1918 influenza pandemic hastened the decline of tuberculosis in the United States: an age, period, cohort analysis. Vaccine 29(Suppl 2):B38–B41CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Noymer A, Garenne M (2000) The 1918 influenza epidemic's effects on sex differentials in mortality in the United States. Popul Dev Rev 26:565–581CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Oei W, Nishiura H (2012) The relationship between tuberculosis and influenza death during the influenza (H1N1) pandemic from 1918-19. Comput Math Methods Med 2012:124861CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Espersen E (1954) Epidemic of influenza B among Greenlandic patients in a Danish tuberculosis sanatorium; influenza and pulmonary tuberculosis. Acta Tuberc Scand 29:125–139PubMedGoogle Scholar
  40. 40.
    Cobelens F, Nagelkerke N, Fletcher H (2018) The convergent epidemiology of tuberculosis and human cytomegalovirus infection. F1000Res 7:280CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Klein SL, Hodgson A, Robinson DP (2012) Mechanisms of sex disparities in influenza pathogenesis. J Leukoc Biol 92:67–73CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J (2008) Helminth infections: the great neglected tropical diseases. J Clin Invest 118:1311–1321CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chatterjee S, Nutman TB (2015) Helminth-induced immune regulation: implications for immune responses to tuberculosis. PLoS Pathog 11:e1004582CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bernin H, Lotter H (2014) Sex bias in the outcome of human tropical infectious diseases: influence of steroid hormones. J Infect Dis 209(Suppl 3):S107–S113CrossRefPubMedGoogle Scholar
  45. 45.
    Klein SL (2004) Hormonal and immunological mechanisms mediating sex differences in parasite infection. Parasite Immunol 26:247–264CrossRefPubMedGoogle Scholar
  46. 46.
    Li XX, Chen JX, Wang LX, Tian LG, Zhang YP, Dong SP, Hu XG, Liu J, Wang FF, Wang Y, Yin XM, He LJ, Yan QY, Zhang HW, Xu BL, Zhou XN (2014) Intestinal parasite co-infection among pulmonary tuberculosis cases without human immunodeficiency virus infection in a rural county in China. Am J Trop Med Hyg 90:106–113CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Li XX, Zhou XN (2013) Co-infection of tuberculosis and parasitic diseases in humans: a systematic review. Parasit Vectors 6:79CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Alemu G, Mama M (2017) Intestinal helminth co-infection and associated factors among tuberculosis patients in Arba Minch, Ethiopia. BMC Infect Dis 17:68CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Babu S, Nutman TB (2016) Helminth-tuberculosis co-infection: an immunologic perspective. Trends Immunol 37:597–607CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Maizels RM, McSorley HJ (2016) Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol 138:666–675CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Elias D, Akuffo H, Britton S (2006) Helminthes could influence the outcome of vaccines against TB in the tropics. Parasite Immunol 28:507–513CrossRefPubMedGoogle Scholar
  52. 52.
    Wammes LJ, Hamid F, Wiria AE, de Gier B, Sartono E, Maizels RM, Luty AJ, Fillie Y, Brice GT, Supali T, Smits HH, Yazdanbakhsh M (2010) Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum. Eur J Immunol 40:437–442CrossRefPubMedGoogle Scholar
  53. 53.
    Elias D, Wolday D, Akuffo H, Petros B, Bronner U, Britton S (2001) Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette-Guerin (BCG) vaccination. Clin Exp Immunol 123:219–225CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Elias D, Britton S, Aseffa A, Engers H, Akuffo H (2008) Poor immunogenicity of BCG in helminth infected population is associated with increased in vitro TGF-beta production. Vaccine 26:3897–3902CrossRefPubMedGoogle Scholar
  55. 55.
    Babu S, Bhat SQ, Kumar NP, Jayantasri S, Rukmani S, Kumaran P, Gopi PG, Kolappan C, Kumaraswami V, Nutman TB (2009) Human type 1 and 17 responses in latent tuberculosis are modulated by coincident filarial infection through cytotoxic T lymphocyte antigen-4 and programmed death-1. J Infect Dis 200:288–298CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Resende Co T, Hirsch CS, Toossi Z, Dietze R, Ribeiro-Rodrigues R (2007) Intestinal helminth co-infection has a negative impact on both anti-Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy. Clin Exp Immunol 147:45–52PubMedPubMedCentralGoogle Scholar
  57. 57.
    Elias D, Akuffo H, Pawlowski A, Haile M, Schon T, Britton S (2005) Schistosoma mansoni infection reduces the protective efficacy of BCG vaccination against virulent Mycobacterium tuberculosis. Vaccine 23:1326–1334CrossRefPubMedGoogle Scholar
  58. 58.
    Potian JA, Rafi W, Bhatt K, McBride A, Gause WC, Salgame P (2011) Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway. J Exp Med 208:1863–1874CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Monin L, Griffiths KL, Lam WY, Gopal R, Kang DD, Ahmed M, Rajamanickam A, Cruz-Lagunas A, Zuniga J, Babu S, Kolls JK, Mitreva M, Rosa BA, Ramos-Payan R, Morrison TE, Murray PJ, Rangel-Moreno J, Pearce EJ, Khader SA (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest 125:4699–4713CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Doolan DL, Dobano C, Baird JK (2009) Acquired immunity to malaria. Clin Microbiol Rev 22:13–36 Table of ContentsCrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Pathak S, Rege M, Gogtay NJ, Aigal U, Sharma SK, Valecha N, Bhanot G, Kshirsagar NA, Sharma S (2012) Age-dependent sex bias in clinical malarial disease in hypoendemic regions. PLoS One 7:e35592CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Haque U, Sunahara T, Hashizume M, Shields T, Yamamoto T, Haque R, Glass GE (2011) Malaria prevalence, risk factors and spatial distribution in a hilly forest area of Bangladesh. PLoS One 6:e18908CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cucunuba ZM, Guerra A, Rivera JA, Nicholls RS (2013) Comparison of asymptomatic Plasmodium spp. infection in two malaria-endemic Colombian locations. Trans R Soc Trop Med Hyg 107:129–136CrossRefPubMedGoogle Scholar
  64. 64.
    Cernetich A, Garver LS, Jedlicka AE, Klein PW, Kumar N, Scott AL, Klein SL (2006) Involvement of gonadal steroids and gamma interferon in sex differences in response to blood-stage malaria infection. Infect Immun 74:3190–3203CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Krucken J, Dkhil MA, Braun JV, Schroetel RM, El-Khadragy M, Carmeliet P, Mossmann H, Wunderlich F (2005) Testosterone suppresses protective responses of the liver to blood-stage malaria. Infect Immun 73:436–443CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Schmitt-Wrede HP, Fiebig S, Wunderlich F, Benten WP, Bettenhauser U, Boden K, Mossmann H (1991) Testosterone-induced susceptibility to Plasmodium chabaudi malaria: variant protein expression in functionally changed splenic non-T cells. Mol Cell Endocrinol 76:207–214CrossRefPubMedGoogle Scholar
  67. 67.
    Wunderlich F, Marinovski P, Benten WP, Schmitt-Wrede HP, Mossmann H (1991) Testosterone and other gonadal factor(s) restrict the efficacy of genes controlling resistance to Plasmodium chabaudi malaria. Parasite Immunol 13:357–367CrossRefPubMedGoogle Scholar
  68. 68.
    Chen I, Clarke SE, Gosling R, Hamainza B, Killeen G, Magill A, O'Meara W, Price RN, Riley EM (2016) “Asymptomatic” malaria: a chronic and debilitating infection that should be treated. PLoS Med 13:e1001942CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Whittle HC, Brown J, Marsh K, Greenwood BM, Seidelin P, Tighe H, Wedderburn L (1984) T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312:449–450CrossRefPubMedGoogle Scholar
  70. 70.
    Williamson WA, Greenwood BM (1978) Impairment of the immune response to vaccination after acute malaria. Lancet 1:1328–1329CrossRefPubMedGoogle Scholar
  71. 71.
    Hviid L, Theander TG, Abu-Zeid YA, Abdulhadi NH, Jakobsen PH, Saeed BO, Jepsen S, Bayoumi RA, Jensen JB (1991) Loss of cellular immune reactivity during acute Plasmodium falciparum malaria. FEMS Microbiol Immunol 3:219–227CrossRefPubMedGoogle Scholar
  72. 72.
    Cook IF (1985) Herpes zoster in children following malaria. J Trop Med Hyg 88:261–264PubMedGoogle Scholar
  73. 73.
    Bomford R, Wedderburn N (1973) Depression of immune response to Moloney leukaemia virus by malarial infection. Nature 242:471–473CrossRefPubMedGoogle Scholar
  74. 74.
    Cunnington AJ, Riley EM (2010) Suppression of vaccine responses by malaria: insignificant or overlooked? Expert Rev Vaccines 9:409–429CrossRefPubMedGoogle Scholar
  75. 75.
    Walther B, Miles DJ, Waight P, Palmero MS, Ojuola O, Touray ES, Whittle H, van der Sande M, Crozier S, Flanagan KL (2012) Placental malaria is associated with attenuated CD4 T-cell responses to tuberculin PPD 12 months after BCG vaccination. BMC Infect Dis 12:6CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Scott JA, Berkley JA, Mwangi I, Ochola L, Uyoga S, Macharia A, Ndila C, Lowe BS, Mwarumba S, Bauni E, Marsh K, Williams TN (2011) Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study. Lancet 378:1316–1323CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Colombatti R, Penazzato M, Bassani F, Vieira CS, Lourenco AA, Vieira F, Teso S, Giaquinto C, Riccardi F (2011) Malaria prevention reduces in-hospital mortality among severely ill tuberculosis patients: a three-step intervention in Bissau, Guinea-Bissau. BMC Infect Dis 11:57CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Blank J, Eggers L, Behrends J, Jacobs T, Schneider BE (2016) One episode of self-resolving Plasmodium yoelii infection transiently exacerbates chronic Mycobacterium tuberculosis infection. Front Microbiol 7:152CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Mueller A-K, Behrends J, Hagens K, Mahlo J, Schaible UE, Schneider BE (2012) Natural transmission of Plasmodium berghei exacerbates chronic tuberculosis in an experimental co-infection model. PLoS One 7:e48110CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Scott CP, Kumar N, Bishai WR, Manabe YC (2004) Short report: modulation of Mycobacterium tuberculosis infection by Plasmodium in the murine model. Am J Trop Med Hyg 70:144–148CrossRefPubMedGoogle Scholar
  81. 81.
    Hawkes M, Li X, Crockett M, Diassiti A, Conrad Liles W, Liu J, Kain KC (2010) Malaria exacerbates experimental mycobacterial infection in vitro and in vivo. Microbes Infect 12:864–874CrossRefPubMedGoogle Scholar
  82. 82.
    Leisewitz AL, Rockett K, Kwiatkowski D (2008) BCG-malaria co-infection has paradoxical effects on C57BL/6 and A/J mouse strains. Parasite Immunol 30:1–12CrossRefPubMedGoogle Scholar
  83. 83.
    Falagas ME, Mourtzoukou EG, Vardakas KZ (2007) Sex differences in the incidence and severity of respiratory tract infections. Respir Med 101:1845–1863CrossRefPubMedGoogle Scholar
  84. 84.
    Gutierrez F, Masia M, Mirete C, Soldan B, Rodriguez JC, Padilla S, Hernandez I, Royo G, Martin-Hidalgo A (2006) The influence of age and gender on the population-based incidence of community-acquired pneumonia caused by different microbial pathogens. J Inf Secur 53:166–174Google Scholar
  85. 85.
    Loeb M, McGeer A, McArthur M, Walter S, Simor AE (1999) Risk factors for pneumonia and other lower respiratory tract infections in elderly residents of long-term care facilities. Arch Intern Med 159:2058–2064CrossRefPubMedGoogle Scholar
  86. 86.
    European Centre for Disease Prevention and Control (2009) Legionnaires’ disease in Europe. ECDC, Stockholm.
  87. 87.
    Neil K, Berkelman R (2008) Increasing incidence of legionellosis in the United States, 1990–2005: changing epidemiologic trends. Clin Infect Dis 47:591–599CrossRefPubMedGoogle Scholar
  88. 88.
    Kadioglu A, Cuppone AM, Trappetti C, List T, Spreafico A, Pozzi G, Andrew PW, Oggioni MR (2011) Sex-based differences in susceptibility to respiratory and systemic pneumococcal disease in mice. J Infect Dis 204:1971–1979CrossRefPubMedGoogle Scholar
  89. 89.
    Yang Z, Huang YC, Koziel H, de Crom R, Ruetten H, Wohlfart P, Thomsen RW, Kahlert JA, Sorensen HT, Jozefowski S, Colby A, Kobzik L (2014) Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target. Elife 3.
  90. 90.
    Yancey AL, Watson HL, Cartner SC, Simecka JW (2001) Gender is a major factor in determining the severity of mycoplasma respiratory disease in mice. Infect Immun 69:2865–2871CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Chamekh M, Deny M, Romano M, Lefevre N, Corazza F, Duchateau J, Casimir G (2017) Differential susceptibility to infectious respiratory diseases between males and females linked to sex-specific innate immune inflammatory response. Front Immunol 8:1806CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    IH YH-PaC (2015) Sex differences in sepsis following trauma and injury in sex and gender differences in infection and treatments for infectious diseases. Springer, VerlagGoogle Scholar
  93. 93.
    Speyer CL, Rancilio NJ, McClintock SD, Crawford JD, Gao H, Sarma JV, Ward PA (2005) Regulatory effects of estrogen on acute lung inflammation in mice. Am J Physiol Cell Physiol 288:C881–C890CrossRefPubMedGoogle Scholar
  94. 94.
    Brown IN, Glynn AA (1987) The Ity/Lsh/Bcg gene significantly affects mouse resistance to Mycobacterium lepraemurium. Immunology 62:587–591PubMedPubMedCentralGoogle Scholar
  95. 95.
    Curtis J, Turk JL (1984) Resistance to subcutaneous infection with Mycobacterium lepraemurium is controlled by more than one gene. Infect Immun 43:925–930PubMedPubMedCentralGoogle Scholar
  96. 96.
    Yamamoto Y, Saito H, Setogawa T, Tomioka H (1991) Sex differences in host resistance to Mycobacterium marinum infection in mice. Infect Immun 59:4089–4096PubMedPubMedCentralGoogle Scholar
  97. 97.
    Yamamoto Y, Tomioka H, Sato K, Saito H, Yamada Y, Setogawa T (1990) Sex differences in the susceptibility of mice to infection induced by Mycobacterium intracellulare. Am Rev Respir Dis 142:430–433CrossRefPubMedGoogle Scholar
  98. 98.
    Tsuyuguchi K, Suzuki K, Matsumoto H, Tanaka E, Amitani R, Kuze F (2001) Effect of oestrogen on Mycobacterium avium complex pulmonary infection in mice. Clin Exp Immunol 123:428–434CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Jung YJ, Ryan L, LaCourse R, North RJ (2009) Differences in the ability to generate type 1 T helper cells need not determine differences in the ability to resist Mycobacterium tuberculosis infection among mouse strains. J Infect Dis 199:1790–1796CrossRefPubMedGoogle Scholar
  100. 100.
    Bini EI, Mata Espinosa D, Marquina Castillo B, Barrios Payan J, Colucci D, Cruz AF, Zatarain ZL, Alfonseca E, Pardo MR, Bottasso O, Hernandez PR (2014) The influence of sex steroid hormones in the immunopathology of experimental pulmonary tuberculosis. PLoS One 9:e93831CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Dibbern J, Eggers L, Schneider BE (2017) Sex differences in the C57BL/6 model of Mycobacterium tuberculosis infection. Sci Rep 7:10957CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Orme IM, Robinson RT, Cooper AM (2015) The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 16:57–63CrossRefPubMedGoogle Scholar
  103. 103.
    Kleinnijenhuis J, Oosting M, Joosten LA, Netea MG, Van Crevel R (2011) Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol 2011:405310CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Klein SL (2012) Immune cells have sex and so should journal articles. Endocrinology 153:2544–2550CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Jaillon S, Berthenet K, Garlanda C (2017) Sexual dimorphism in innate immunity. Clin Rev Allergy Immunol.
  106. 106.
    Davila S, Hibberd ML, Hari Dass R, Wong HE, Sahiratmadja E, Bonnard C, Alisjahbana B, Szeszko JS, Balabanova Y, Drobniewski F, van Crevel R, van de Vosse E, Nejentsev S, Ottenhoff TH, Seielstad M (2008) Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet 4:e1000218CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Tang J, Sun M, Shi G, Xu Y, Han Y, Li X, Dong W, Zhan L, Qin C (2017) Toll-like receptor 8 agonist strengthens the protective efficacy of ESAT-6 immunization to Mycobacterium tuberculosis infection. Front Immunol 8:1972CrossRefPubMedGoogle Scholar
  108. 108.
    Marriott I, Bost KL, Huet-Hudson YM (2006) Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility. J Reprod Immunol 71:12–27CrossRefPubMedGoogle Scholar
  109. 109.
    Traub S, Demaria O, Chasson L, Serra F, Desnues B, Alexopoulou L (2012) Sex bias in susceptibility to MCMV infection: implication of TLR9. PLoS One 7:e45171CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM (2013) Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nat Immunol 14:52–60CrossRefPubMedGoogle Scholar
  111. 111.
    Zhang G, Zhou B, Li S, Yue J, Yang H, Wen Y, Zhan S, Wang W, Liao M, Zhang M, Zeng G, Feng CG, Sassetti CM, Chen X (2014) Allele-specific induction of IL-1beta expression by C/EBPbeta and PU.1 contributes to increased tuberculosis susceptibility. PLoS Pathog 10:e1004426CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Sakai S, Kauffman KD, Sallin MA, Sharpe AH, Young HA, Ganusov VV, Barber DL (2016) CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog 12:e1005667CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Cadena AM, Flynn JL, Fortune SM (2016) The importance of first impressions: early events in Mycobacterium tuberculosis infection influence outcome. MBio 7:e00342–e00316CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Coleman MT, Maiello P, Tomko J, Frye LJ, Fillmore D, Janssen C, Klein E, Lin PL (2014) Early changes by (18)fluorodeoxyglucose positron emission tomography coregistered with computed tomography predict outcome after Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun 82:2400–2404CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Lin PL, Pawar S, Myers A, Pegu A, Fuhrman C, Reinhart TA, Capuano SV, Klein E, Flynn JL (2006) Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun 74:3790–3803CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16:626–638CrossRefGoogle Scholar
  117. 117.
    Chackerian A, Alt J, Perera V, Behar SM (2002) Activation of NKT cells protects mice from tuberculosis. Infect Immun 70:6302–6309CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Gansert JL, Kiessler V, Engele M, Wittke F, Rollinghoff M, Krensky AM, Porcelli SA, Modlin RL, Stenger S (2003) Human NKT cells express granulysin and exhibit antimycobacterial activity. J Immunol 170:3154–3161CrossRefPubMedGoogle Scholar
  119. 119.
    Rothchild AC, Jayaraman P, Nunes-Alves C, Behar SM (2014) iNKT cell production of GM-CSF controls Mycobacterium tuberculosis. PLoS Pathog 10:e1003805CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Sada-Ovalle I, Skold M, Tian T, Besra GS, Behar SM (2010) Alpha-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 182:841–847CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Sutherland JS, Jeffries DJ, Donkor S, Walther B, Hill PC, Adetifa IM, Adegbola RA, Ota MO (2009) High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting. Tuberculosis (Edinb) 89:398–404CrossRefGoogle Scholar
  122. 122.
    Bernin H, Fehling H, Marggraff C, Tannich E, Lotter H (2016) The cytokine profile of human NKT cells and PBMCs is dependent on donor sex and stimulus. Med Microbiol Immunol 205:321–332CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Gourdy P, Araujo LM, Zhu R, Garmy-Susini B, Diem S, Laurell H, Leite-de-Moraes M, Dy M, Arnal JF, Bayard F, Herbelin A (2005) Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-gamma production by invariant natural killer T cells. Blood 105:2415–2420CrossRefPubMedGoogle Scholar
  124. 124.
    Lotter H, Helk E, Bernin H, Jacobs T, Prehn C, Adamski J, Gonzalez-Roldan N, Holst O, Tannich E (2013) Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNgamma secretion in natural killer T cells. PLoS One 8:e55694CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Sharma S, Eghbali M (2014) Influence of sex differences on microRNA gene regulation in disease. Biol Sex Differ 5:3CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Dai R, Phillips RA, Zhang Y, Khan D, Crasta O, Ahmed SA (2008) Suppression of LPS-induced interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood 112:4591–4597CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Dorhoi A, Iannaccone M, Farinacci M, Fae KC, Schreiber J, Moura-Alves P, Nouailles G, Mollenkopf HJ, Oberbeck-Muller D, Jorg S, Heinemann E, Hahnke K, Lowe D, Del Nonno F, Goletti D, Capparelli R, Kaufmann SH (2013) MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J Clin Invest 123:4836–4848CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Dallenga T, Schaible UE (2016) Neutrophils in tuberculosis--first line of defence or booster of disease and targets for host-directed therapy? Pathog Dis 74.
  129. 129.
    Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV, Orlova MO, Apt AS (2005) Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun 73:1744–1753CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Keller C, Hoffmann R, Lang R, Brandau S, Hermann C, Ehlers S (2006) Genetically determined susceptibility to tuberculosis in mice causally involves accelerated and enhanced recruitment of granulocytes. Infect Immun 74:4295–4309CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Yeremeev V, Linge I, Kondratieva T, Apt A (2015) Neutrophils exacerbate tuberculosis infection in genetically susceptible mice. Tuberculosis (Edinb) 95:447–451CrossRefGoogle Scholar
  132. 132.
    Panteleev AV, Nikitina IY, Burmistrova IA, Kosmiadi GA, Radaeva TV, Amansahedov RB, Sadikov PV, Serdyuk YV, Larionova EE, Bagdasarian TR, Chernousova LN, Ganusov VV, Lyadova IV (2017) Severe tuberculosis in humans correlates best with neutrophil abundance and lymphocyte deficiency and does not correlate with antigen-specific CD4 T-cell response. Front Immunol 8:963CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Barnes PF, Leedom JM, Chan LS, Wong SF, Shah J, Vachon LA, Overturf GD, Modlin RL (1988) Predictors of short-term prognosis in patients with pulmonary tuberculosis. J Infect Dis 158:366–371CrossRefPubMedGoogle Scholar
  134. 134.
    Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, Wilkinson KA, Banchereau R, Skinner J, Wilkinson RJ, Quinn C, Blankenship D, Dhawan R, Cush JJ, Mejias A, Ramilo O, Kon OM, Pascual V, Banchereau J, Chaussabel D, O'Garra A (2010) An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466:973–977CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Sathyamoorthy T, Sandhu G, Tezera LB, Thomas R, Singhania A, Woelk CH, Dimitrov BD, Agranoff D, Evans CA, Friedland JS, Elkington PT (2015) Gender-dependent differences in plasma matrix metalloproteinase-8 elevated in pulmonary tuberculosis. PLoS One 10:e0117605CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Madalli S, Beyrau M, Whiteford J, Duchene J, Singh Nandhra I, Patel NS, Motwani MP, Gilroy DW, Thiemermann C, Nourshargh S, Scotland RS (2015) Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states. Biol Sex Differ 6:27CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    MacKenzie KF, Clark K, Naqvi S, McGuire VA, Noehren G, Kristariyanto Y, van den Bosch M, Mudaliar M, McCarthy PC, Pattison MJ, Pedrioli PG, Barton GJ, Toth R, Prescott A, Arthur JS (2013) PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol 190:565–577CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Na YR, Jung D, Yoon BR, Lee WW, Seok SH (2015) Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-beta cascade. Eur J Immunol 45:2661–2671CrossRefPubMedGoogle Scholar
  139. 139.
    Strassmann G, Patil-Koota V, Finkelman F, Fong M, Kambayashi T (1994) Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. J Exp Med 180:2365–2370CrossRefPubMedGoogle Scholar
  140. 140.
    Saraiva M, O'Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181CrossRefPubMedGoogle Scholar
  141. 141.
    Redford PS, Murray PJ, O'Garra A (2011) The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol 4:261–270CrossRefPubMedGoogle Scholar
  142. 142.
    Cadena AM, Fortune SM, Flynn JL (2017) Heterogeneity in tuberculosis. Nat Rev Immunol 17:691–702CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Kumar P (2016) Adult pulmonary tuberculosis as a pathological manifestation of hyperactive antimycobacterial immune response. Clin Transl Med 5:38CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Chen M, Divangahi M, Gan H, Shin DS, Hong S, Lee DM, Serhan CN, Behar SM, Remold HG (2008) Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 205:2791–2801CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Herbst S, Schaible UE, Schneider BE (2011) Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS One 6:e19105CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan HX, Divangahi M, Remold HG (2011) Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. Mucosal Immunol 4:279–287CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TT, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King MC, Serhan CN, Ramakrishnan L (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434–446CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ (2001) The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med 193:271–280CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Cooper AM (2009) Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 27:393–422CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, Ernst JD (2008) Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med 205:105–115CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM (2002) Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity. Infect Immun 70:4501–4509CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP (2013) The immune response in tuberculosis. Annu Rev Immunol 31:475–527CrossRefPubMedGoogle Scholar
  153. 153.
    Tsai MC, Chakravarty S, Zhu G, Xu J, Tanaka K, Koch C, Tufariello J, Flynn J, Chan J (2006) Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell Microbiol 8:218–232CrossRefPubMedGoogle Scholar
  154. 154.
    Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, Kaushal D, Reinhart TA, Randall TD, Khader SA (2013) CXCR5(+) T helper cells mediate protective immunity against tuberculosis. J Clin Invest 123:712–726PubMedPubMedCentralGoogle Scholar
  155. 155.
    Ulrichs T, Kosmiadi GA, Jorg S, Pradl L, Titukhina M, Mishenko V, Gushina N, Kaufmann SH (2005) Differential organization of the local immune response in patients with active cavitary tuberculosis or with nonprogressive tuberculoma. J Infect Dis 192:89–97CrossRefPubMedGoogle Scholar
  156. 156.
    Khader SA, Guglani L, Rangel-Moreno J, Gopal R, Junecko BA, Fountain JJ, Martino C, Pearl JE, Tighe M, Lin YY, Slight S, Kolls JK, Reinhart TA, Randall TD, Cooper AM (2011) IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung. J Immunol 187:5402–5407CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Zumla A, Rao M, Parida SK, Keshavjee S, Cassell G, Wallis R, Axelsson-Robertsson R, Doherty M, Andersson J, Maeurer M (2015) Inflammation and tuberculosis: host-directed therapies. J Intern Med 277:373–387CrossRefPubMedGoogle Scholar
  158. 158.
    Fish EN (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8:737–744CrossRefPubMedGoogle Scholar
  159. 159.
    Pahari S, Kaur G, Aqdas M, Negi S, Chatterjee D, Bashir H, Singh S, Agrewala JN (2017) Bolstering immunity through pattern recognition receptors: a unique approach to control tuberculosis. Front Immunol 8:906CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Goletti D, Lee MR, Wang JY, Walter N, Ottenhoff THM (2018) Update on tuberculosis biomarkers: from correlates of risk, to correlates of active disease and of cure from disease. Respirology 23:455–466CrossRefPubMedGoogle Scholar
  161. 161.
    Diwan VK, Thorson A (1999) Sex, gender, and tuberculosis. Lancet 353:1000–1001CrossRefPubMedGoogle Scholar
  162. 162.
    Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, Mahomed H, Erasmus M, Whatney W, Hussey GD, Abrahams D, Kafaar F, Hawkridge T, Verver S, Hughes EJ, Ota M, Sutherland J, Howe R, Dockrell HM, Boom WH, Thiel B, Ottenhoff TH, Mayanja-Kizza H, Crampin AC, Downing K, Hatherill M, Valvo J, Shankar S, Parida SK, Kaufmann SH, Walzl G, Aderem A, Hanekom WA, Acs, groups GCcs (2016) A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 387:2312–2322CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Weiner J 3rd, Parida SK, Maertzdorf J, Black GF, Repsilber D, Telaar A, Mohney RP, Arndt-Sullivan C, Ganoza CA, Fae KC, Walzl G, Kaufmann SH (2012) Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS One 7:e40221CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Piasecka B, Duffy D, Urrutia A, Quach H, Patin E, Posseme C, Bergstedt J, Charbit B, Rouilly V, MacPherson CR, Hasan M, Albaud B, Gentien D, Fellay J, Albert ML, Quintana-Murci L, Milieu Interieur C (2018) Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. Proc Natl Acad Sci U S A 115:E488–EE97CrossRefPubMedGoogle Scholar
  165. 165.
    Krumsiek J, Mittelstrass K, Do KT, Stuckler F, Ried J, Adamski J, Peters A, Illig T, Kronenberg F, Friedrich N, Nauck M, Pietzner M, Mook-Kanamori DO, Suhre K, Gieger C, Grallert H, Theis FJ, Kastenmuller G (2015) Gender-specific pathway differences in the human serum metabolome. Metabolomics 11:1815–1833CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Coinfection Unit, Priority Research Area InfectionsResearch Center BorstelBorstelGermany

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