The Role of Sex Steroid Hormones in CD4+ T Cell-mediated Immune Responses to Tuberculosis

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ABSTRACT The goal of this Fogarty K43 Global Emerging Leader award is to establish Djeneba Dabitao, PharmD, PhD, as a leading, independent investigator and future mentor in research focused on the role of sex differences in immune responses, disease susceptibility, and treatment outcomes of infectious diseases, particularly in tuberculosis (TB). The field of sex-based biology is rapidly expanding with strong evidence showing that men and women respond differently to microbial challenges, therapeutics, and vaccines. I have chosen to focus on TB because it remains a leading public health problem in poor nations such as Mali in West Africa. Indeed, in this region the incidence of TB in men is, on average, 2 to 3 times higher than women. Yet, despite compelling data indicating that male sex is an independent risk factor for developing active pulmonary TB (TB+), little is known about the underlying mechanisms of increased prevalence in males compared to females. I hypothesize that sex hormones influence CD4+ T cell-mediated immune responses to TB. To test this hypothesis, I will assess differences in immune response between men and women with TB+ (Aim 1) and compare the effects of sex steroid hormones on immune responses between men and women with TB+ ex vivo (Aim 2). The research plan is well aligned with existing, joint research activities between the Université des Sciences, Techniques, et Technologies of Bamako (USTTB) in Mali, Northwestern University (NU) and the Johns Hopkins University (JHU) in the US, which include an R01 on host-pathogen interaction during Mycobacterium africanum infection (R01AI110386; PI: Diallo) and a Fogarty International Center training grant on HIV and mycobacterial diseases (D43TW010350, co-PIs: Diallo and Murphy). I will also leverage the exceptional BSL3 and ImmunoCore facilities and resources, available at the University Clinical Research Center (UCRC), funded by NIAID, under the leadership of Clifford Lane, MD and Seydou Doumbia, MD PhD. For this K43, I will pursue didactic, structured tutorial, and experiential laboratory training to assure acquisition of expertise in four essential areas for me to become a leader in the field of sex differences in disease susceptibility, therapeutics, and potentially vaccine development, namely: (1) immuno-endocrinology, (2) mycobacteriology, (3) epidemiology, biostatistics, and research study design, and (4) grant and manuscript preparation and effective scientific presentation. I have an excellent, multidisciplinary mentoring team of experts from Mali and the US, including Co-Primary Mentors, Souleymane Diallo, MD (USTTB) and Robert Murphy, MD (NU); William Bishai, MD PhD (JHU), expert in mycobacteriology; Sabra Klein, PhD (JHU), for training in immuno-endocrinology; Chad Achenbach, MD MPH (NU), for epidemiology, biostatistics, and research study design; Jane L. Holl, MD MPH (NU), for scientific writing (grant and manuscript) and presentation training.