Abstract
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.
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References
WHO (2017) Global tuberculosis report 2017. World Health Organization, Geneva.
Holmes CB, Hausler H, Nunn P (1998) A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 2:96–104
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 57:398–402
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 369:1955–1960
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 3:388–393
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 4:123–132
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:e1002119
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 88:273–280
Centers for Disease Control and Prevention (CDC) (2017) Reported tuberculosis in the United States, 2016. US Department of Health and Human Services, Atlanta, GA
Bericht zur Epidemiologie der Tuberkulose in Deutschland für 2016. https://doi.org/10.17886/rkipubl-2017-004
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 15:165
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:e0141511
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 18:266
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:e110104
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 11:89
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. https://doi.org/10.1007/s15010-016-0963-2
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 194:493–500
Nhamoyebonde S, Leslie A (2014) Biological differences between the sexes and susceptibility to tuberculosis. J Infect Dis 209(Suppl 3):S100–S106
Rees D, Murray J (2007) Silica, silicosis and tuberculosis. Int J Tuberc Lung Dis 11:474–484
Narasimhan P, Wood J, Macintyre CR, Mathai D (2013) Risk factors for tuberculosis. Pulm Med 2013:828939
Watkins RE, Plant AJ (2006) Does smoking explain sex differences in the global tuberculosis epidemic? Epidemiol Infect 134:333–339
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 167:335–342
Maurya V, Vijayan VK, Shah A (2002) Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis 6:942–951
Wilsnack RW, Wilsnack SC, Kristjanson AF, Vogeltanz-Holm ND, Gmel G (2009) Gender and alcohol consumption: patterns from the multinational GENACIS project. Addiction 104:1487–1500
Development PCfHRa (2016) National tuberculosis prevalence survey 2016 Philippines
WHO (2016) Tuberculosis in women. http://www.who.int/tb/publications/tb_women_factsheet_251013.pdf. Accessed 28 May 2018
Mathad JS, Gupta A (2012) Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect Dis 55:1532–1549
Loto OM, Awowole I (2012) Tuberculosis in pregnancy: a review. J Pregnancy 2012:379271
Klein S, Roberts C, Editors (2015) Sex and gender differences in infection and treatments for infectious diseases. Springer, Verlag
McClelland EE, Smith JM (2011) Gender specific differences in the immune response to infection. Arch Immunol Ther Exp 59:203–213
Pawlowski A, Jansson M, Skold M, Rottenberg ME, Kallenius G (2012) Tuberculosis and HIV co-infection. PLoS Pathog 8:e1002464
Addo MM, Altfeld M (2014) Sex-based differences in HIV type 1 pathogenesis. J Infect Dis 209(Suppl 3):S86–S92
Kanabus A (2017) Information about tuberculosis GHE, 2017. www.tbfacts.org
Janet F (2010) Tackling TB and HIV in Women: An Urgent Agenda. https://www.mchip.net/sites/default/files/Tackling-TB-and-HIV-in-Women.pdf. Accessed 29 May 2018
WHO (2009) WHO information on tuberculosis and pandemic influenza A (H1N1). http://www.who.int/tb/features_archive/h1n1/en/. Accessed 30 January 2015
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–B41
Noymer A, Garenne M (2000) The 1918 influenza epidemic's effects on sex differentials in mortality in the United States. Popul Dev Rev 26:565–581
Oei W, Nishiura H (2012) The relationship between tuberculosis and influenza death during the influenza (H1N1) pandemic from 1918-19. Comput Math Methods Med 2012:124861
Espersen E (1954) Epidemic of influenza B among Greenlandic patients in a Danish tuberculosis sanatorium; influenza and pulmonary tuberculosis. Acta Tuberc Scand 29:125–139
Cobelens F, Nagelkerke N, Fletcher H (2018) The convergent epidemiology of tuberculosis and human cytomegalovirus infection. F1000Res 7:280
Klein SL, Hodgson A, Robinson DP (2012) Mechanisms of sex disparities in influenza pathogenesis. J Leukoc Biol 92:67–73
Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J (2008) Helminth infections: the great neglected tropical diseases. J Clin Invest 118:1311–1321
Chatterjee S, Nutman TB (2015) Helminth-induced immune regulation: implications for immune responses to tuberculosis. PLoS Pathog 11:e1004582
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–S113
Klein SL (2004) Hormonal and immunological mechanisms mediating sex differences in parasite infection. Parasite Immunol 26:247–264
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 90:106–113
Li XX, Zhou XN (2013) Co-infection of tuberculosis and parasitic diseases in humans: a systematic review. Parasit Vectors 6:79
Alemu G, Mama M (2017) Intestinal helminth co-infection and associated factors among tuberculosis patients in Arba Minch, Ethiopia. BMC Infect Dis 17:68
Babu S, Nutman TB (2016) Helminth-tuberculosis co-infection: an immunologic perspective. Trends Immunol 37:597–607
Maizels RM, McSorley HJ (2016) Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol 138:666–675
Elias D, Akuffo H, Britton S (2006) Helminthes could influence the outcome of vaccines against TB in the tropics. Parasite Immunol 28:507–513
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 40:437–442
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 123:219–225
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 26:3897–3902
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 200:288–298
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 147:45–52
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 23:1326–1334
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 208:1863–1874
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 125:4699–4713
Doolan DL, Dobano C, Baird JK (2009) Acquired immunity to malaria. Clin Microbiol Rev 22:13–36 Table of Contents
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:e35592
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:e18908
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 107:129–136
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 74:3190–3203
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 73:436–443
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 76:207–214
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 13:357–367
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:e1001942
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 312:449–450
Williamson WA, Greenwood BM (1978) Impairment of the immune response to vaccination after acute malaria. Lancet 1:1328–1329
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 3:219–227
Cook IF (1985) Herpes zoster in children following malaria. J Trop Med Hyg 88:261–264
Bomford R, Wedderburn N (1973) Depression of immune response to Moloney leukaemia virus by malarial infection. Nature 242:471–473
Cunnington AJ, Riley EM (2010) Suppression of vaccine responses by malaria: insignificant or overlooked? Expert Rev Vaccines 9:409–429
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 12:6
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 378:1316–1323
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 11:57
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 7:152
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:e48110
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 70:144–148
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 12:864–874
Leisewitz AL, Rockett K, Kwiatkowski D (2008) BCG-malaria co-infection has paradoxical effects on C57BL/6 and A/J mouse strains. Parasite Immunol 30:1–12
Falagas ME, Mourtzoukou EG, Vardakas KZ (2007) Sex differences in the incidence and severity of respiratory tract infections. Respir Med 101:1845–1863
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 53:166–174
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 159:2058–2064
European Centre for Disease Prevention and Control (2009) Legionnaires’ disease in Europe. ECDC, Stockholm. https://doi.org/10.2900/58495
Neil K, Berkelman R (2008) Increasing incidence of legionellosis in the United States, 1990–2005: changing epidemiologic trends. Clin Infect Dis 47:591–599
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 204:1971–1979
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. https://doi.org/10.7554/eLife.03711
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 69:2865–2871
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 8:1806
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, Verlag
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–C890
Brown IN, Glynn AA (1987) The Ity/Lsh/Bcg gene significantly affects mouse resistance to Mycobacterium lepraemurium. Immunology 62:587–591
Curtis J, Turk JL (1984) Resistance to subcutaneous infection with Mycobacterium lepraemurium is controlled by more than one gene. Infect Immun 43:925–930
Yamamoto Y, Saito H, Setogawa T, Tomioka H (1991) Sex differences in host resistance to Mycobacterium marinum infection in mice. Infect Immun 59:4089–4096
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 142:430–433
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 123:428–434
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 199:1790–1796
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:e93831
Dibbern J, Eggers L, Schneider BE (2017) Sex differences in the C57BL/6 model of Mycobacterium tuberculosis infection. Sci Rep 7:10957
Orme IM, Robinson RT, Cooper AM (2015) The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 16:57–63
Kleinnijenhuis J, Oosting M, Joosten LA, Netea MG, Van Crevel R (2011) Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol 2011:405310
Klein SL (2012) Immune cells have sex and so should journal articles. Endocrinology 153:2544–2550
Jaillon S, Berthenet K, Garlanda C (2017) Sexual dimorphism in innate immunity. Clin Rev Allergy Immunol. https://doi.org/10.1007/s12016-017-8648-x
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:e1000218
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 8:1972
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 71:12–27
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:e45171
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 14:52–60
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:e1004426
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:e1005667
Cadena AM, Flynn JL, Fortune SM (2016) The importance of first impressions: early events in Mycobacterium tuberculosis infection influence outcome. MBio 7:e00342–e00316
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 82:2400–2404
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 74:3790–3803
Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16:626–638
Chackerian A, Alt J, Perera V, Behar SM (2002) Activation of NKT cells protects mice from tuberculosis. Infect Immun 70:6302–6309
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 170:3154–3161
Rothchild AC, Jayaraman P, Nunes-Alves C, Behar SM (2014) iNKT cell production of GM-CSF controls Mycobacterium tuberculosis. PLoS Pathog 10:e1003805
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 182:841–847
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) 89:398–404
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 205:321–332
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 105:2415–2420
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:e55694
Sharma S, Eghbali M (2014) Influence of sex differences on microRNA gene regulation in disease. Biol Sex Differ 5:3
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 112:4591–4597
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 123:4836–4848
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. https://doi.org/10.1093/femspd/ftw012
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 73:1744–1753
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 74:4295–4309
Yeremeev V, Linge I, Kondratieva T, Apt A (2015) Neutrophils exacerbate tuberculosis infection in genetically susceptible mice. Tuberculosis (Edinb) 95:447–451
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 8:963
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 158:366–371
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 466:973–977
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:e0117605
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 6:27
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 190:565–577
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 45:2661–2671
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 180:2365–2370
Saraiva M, O'Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181
Redford PS, Murray PJ, O'Garra A (2011) The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol 4:261–270
Cadena AM, Fortune SM, Flynn JL (2017) Heterogeneity in tuberculosis. Nat Rev Immunol 17:691–702
Kumar P (2016) Adult pulmonary tuberculosis as a pathological manifestation of hyperactive antimycobacterial immune response. Clin Transl Med 5:38
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 205:2791–2801
Herbst S, Schaible UE, Schneider BE (2011) Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS One 6:e19105
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 4:279–287
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 148:434–446
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 193:271–280
Cooper AM (2009) Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 27:393–422
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 205:105–115
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 70:4501–4509
O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP (2013) The immune response in tuberculosis. Annu Rev Immunol 31:475–527
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 8:218–232
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 123:712–726
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 192:89–97
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 187:5402–5407
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 277:373–387
Fish EN (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8:737–744
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 8:906
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 23:455–466
Diwan VK, Thorson A (1999) Sex, gender, and tuberculosis. Lancet 353:1000–1001
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 387:2312–2322
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:e40221
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–EE97
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 11:1815–1833
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We thank Jochen Behrends and Ulrich Schaible for critical discussions and helpful comments on the manuscript.
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This article is a contribution to the special issue on Sex differences in immunity – Guest Editors: Hanna Lotter and Marcus Altfeld
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Hertz, D., Schneider, B. Sex differences in tuberculosis. Semin Immunopathol 41, 225–237 (2019). https://doi.org/10.1007/s00281-018-0725-6
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DOI: https://doi.org/10.1007/s00281-018-0725-6