Kenya

Infection with Mycobacterium tuberculosis (Mtb) results in 10 million cases of active tuberculosis (TB) disease each year and it’s the leading cause of death due to a single infectious agent. Although the correlates of protective immunity to Mtb are not clearly defined, co-infection with human immunodeficiency virus (HIV) is a significant risk factor for development of active TB disease. The focus of this proposal is to determine the effect of HIV infection and treatment on the phenotype, function, epigenome, and transcriptome of CD4 T cell responses to Mtb. This study will leverage blood samples collected from a unique, well-characterized longitudinal cohort of women at high-risk for HIV infection in Mombasa, Kenya to test the hypothesis that (i) HIV infection modifies the epigenome and transcriptome of CD4 T cells to promote differentiation of dysfunctional CD4 T cells; and (ii) early initiation of antiretroviral therapy (ART), prior to HIV-induced CD4 T cell deficiency, preserves the molecular program and functional capacity of CD4 T cell responses that may contribute to enhanced immune control of Mtb.

This proposal describes a 5-year training and research plan that will allow Lisa Cranmer, MD, MPH to build on her background in global pediatric TB/HIV and molecular epidemiology and gain critical skills in immunology and advanced biostatistics. Dr. Cranmer will develop additional skills in: 1) humoral and innate immunology methods, 2) advanced longitudinal data analysis, and 3) vaccinology. Dr. Cranmer will leverage her substantive field research experience in Kenya using ongoing cohorts of mother-infant pairs. Current strategies to prevent Mtb infection in HEU infants, including BCG vaccination and primary isoniazid preventive therapy, have not been successful. In order to design new prevention strategies, Dr. Cranmer will evaluate the role of antibodies in protection of HEU infants form Mtb infection and examine if maternal HIV exposure leads to changes in infant Mtb antibody-mediated innate immunity.

With the support of this K23 award, Dr. Sara Auld will address the question of how HIV infection impacts the response to TB exposure. She will first leverage data generated by the screening protocols of the Emory/NYU TB Research Unit to determine how HIV affects the acquisition of TB infection among household contacts of TB patients in Kisumu, Kenya (Aim 1). Next, levels of pro-inflammatory, anti-inflammatory, and regulatory cytokines generated by TB-specific T cells, and the phenotype of those cells will be compared for household contacts with and without HIV (Aim 2). Finally, pulmonary immune responses to TB will be compared for people with and without HIV using research bronchoscopy in a separate cohort in Atlanta, GA (Aim 3). Knowledge gained from this study will translate into interventions to decrease the risk of TB infection and improve long-term outcomes for people with HIV.

Helminth infections can modulate immunity to Mycobacterium tuberculosis (Mtb). However, the effect of helminths, including Schistosoma mansoni (SM), on Mtb infection outcomes is less clear. Furthermore, HIV is a known risk factor for tuberculosis (TB) disease and has been implicated in SM pathogenesis. Therefore, it is important to evaluate whether HIV modifies the association between SM and Mtb infection. HIV-infected and HIV-uninfected adults were enrolled in Kisumu County, Kenya between 2014-2017 and categorized into 3 groups based on Mtb infection status: Mtb-uninfected healthy controls, latent TB infection (LTBI), and active TB disease. Participants were subsequently evaluated for infection with SM. We provide evidence that SM infection is associated with a higher probability of active TB disease, particularly in HIV-infected individuals.

Tuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays. Non-sputum-based assays are needed to improve tuberculosis diagnosis and tuberculosis treatment and monitoring. Our aim in this study was to determine whether ultrasensitive detection of Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA) in blood can diagnose tuberculosis and evaluate tuberculosis treatment responses. In this molecular diagnostic study, we analyzed archived serum from two patient populations evaluated for tuberculosis in Eswatini and Kenya to detect Mtb-cfDNA, analyzing serum from all individuals who has both sufficient serum volumes and clear diagnostic results. The findings were that CRISPR-mediated detection of circulating Mtb-cfDNA shows promise to increase the identification of pediatric tuberculosis and HIV-associated tuberculosis, and potential for early diagnosis and rapid monitoring of tuberculosis treatment responses.