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https://www.arca.fiocruz.br/handle/icict/48078
INTEGRATIVE MULTI-OMICS REVEALS SERUM MARKERS OF TUBERCULOSIS IN ADVANCED HIV
Author
Affilliation
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India / Johns Hopkins Bloomberg School of Public Health. Department of International Health. Baltimore, MD, United States.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India.
University of Pennsylvania. Perelman School of Medicine. Department of Medicine. Division of Infectious Diseases. Philadelphia, PA, United States.
College of Medicine-Johns Hopkins Project. Blantyre, Malawi.
University of KwaZulu-Natal. Centre for the AIDS Programme of Research in South Africa. Nelson R. Mandela School of Medicine. College of Health Sciences. Durban, South Africa / University of KwaZulu-Natal. Doris Duke Medical Research Institute. South African Medical Research Council Pathogenesis and Treatment Research Unit. Durban, South Africa.
University of the Witwatersrand. Perinatal HIV Research Unit. Johannesburg, South Africa.
Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India.
Enhancing Care Foundation. Durban International Clinical Research Site. Durban, South Africa.
Asociacion Civil Impacta Salud y Educacion. Lima, Peru.
University of North Carolina. Project-Malawi. Lilongwe, Malawi / University of North Carolina. Department of Medicine. Division of Infectious Diseases. Chapel Hill, NC, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Escola Bahiana de Medicina e Saúde Pública. Curso de Medicina. Salvador, BA, Brasil.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins Bloomberg School of Public Health. Department of International Health. Baltimore, MD, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India / Johns Hopkins Bloomberg School of Public Health. Department of International Health. Baltimore, MD, United States.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India.
University of Pennsylvania. Perelman School of Medicine. Department of Medicine. Division of Infectious Diseases. Philadelphia, PA, United States.
College of Medicine-Johns Hopkins Project. Blantyre, Malawi.
University of KwaZulu-Natal. Centre for the AIDS Programme of Research in South Africa. Nelson R. Mandela School of Medicine. College of Health Sciences. Durban, South Africa / University of KwaZulu-Natal. Doris Duke Medical Research Institute. South African Medical Research Council Pathogenesis and Treatment Research Unit. Durban, South Africa.
University of the Witwatersrand. Perinatal HIV Research Unit. Johannesburg, South Africa.
Johns Hopkins University Clinical Research Site. Byramjee Jeejeebhoy Government Medical College. Pune, India.
Enhancing Care Foundation. Durban International Clinical Research Site. Durban, South Africa.
Asociacion Civil Impacta Salud y Educacion. Lima, Peru.
University of North Carolina. Project-Malawi. Lilongwe, Malawi / University of North Carolina. Department of Medicine. Division of Infectious Diseases. Chapel Hill, NC, United States.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Escola Bahiana de Medicina e Saúde Pública. Curso de Medicina. Salvador, BA, Brasil.
Johns Hopkins University School of Medicine. Center for Clinical Global Health Education and Center for Tuberculosis Research. Department of Medicine. Division of Infectious Diseases. Baltimore, MD, United States / Johns Hopkins Bloomberg School of Public Health. Department of International Health. Baltimore, MD, United States.
Abstract
Tuberculosis (TB) accounts for disproportionate morbidity and mortality among persons living with HIV (PLWH). Conventional methods of TB diagnosis, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in PLWH. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in very advanced HIV. We conducted a case-control study leveraging REMEMBER, a multi-country, open-label randomized controlled trial comparing 4-drug empiric standard TB treatment with isoniazid preventive therapy in PLWH initiating antiretroviral therapy (ART) with CD4 cell counts <50 cells/mL. Twenty-three cases of incident TB were site-matched with 32 controls to identify microRNAs (miRNAs), metabolites, and cytokines/chemokines, associated with the development of newly diagnosed TB in PLWH. Differentially expressed miRNA analysis revealed 11 altered miRNAs with a fold change higher than 1.4 or lower than -1.4 in cases relative to controls (p<0.05). Our analysis revealed no differentially abundant metabolites between cases and controls. We found higher TNFa and IP-10/CXCL10 in cases (p=0.011, p=0.0005), and higher MDC/CCL22 in controls (p=0.0072). A decision-tree algorithm identified gamma-glutamylthreonine and hsa-miR215-5p as the optimal variables to classify incident TB cases (AUC 0.965; 95% CI 0.925-1.000). hsa-miR-215-5p, which targets genes in the TGF-b signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases. To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed PLWH.
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