Plasma host protein biomarkers correlating with increasing Mycobacterium tuberculosis infection activity prior to tuberculosis diagnosis in people living with HIV
Sarah N. Singer,
Okechukwu C. Ndumnego,
Ryung S. Kim,
Thumbi Ndung'u,
Kathryn Anastos,
Audrey French,
Gavin Churchyard,
Eustache Paramithiothis,
Victoria O. Kasprowicz,
Jacqueline M. Achkar
Affiliations
Sarah N. Singer
Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Okechukwu C. Ndumnego
Africa Health Research Institute, Durban 4013, South Africa
Ryung S. Kim
Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Thumbi Ndung'u
Africa Health Research Institute, Durban 4013, South Africa; HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA; Max Planck Institute of Infection Biology, Berlin, Germany; Division of Infection and Immunity, University College London, London, UK
Kathryn Anastos
Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Audrey French
Department of Medicine, Stroger Hospital of Cook County, Chicago, IL, USA
Gavin Churchyard
Aurum Institute, Johannesburg, South Africa; School of Public Health, University of Witwatersrand, Johannesburg, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA
Africa Health Research Institute, Durban 4013, South Africa; HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA
Jacqueline M. Achkar
Departments of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Corresponding author at: Departments of Medicine (Div. of Infectious Diseases), and Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Block Bld., Rm. 115, Bronx, New York 10461, USA.
Summary: Background: Biomarkers correlating with Mycobacterium tuberculosis infection activity/burden in asymptomatic individuals are urgently needed to identify and treat those at highest risk for developing active tuberculosis (TB). Our main objective was to identify plasma host protein biomarkers that change over time prior to developing TB in people living with HIV (PLHIV). Methods: Using multiplex MRM-MS, we investigated host protein expressions from 2 years before until time of TB diagnosis in longitudinally collected (every 3-6 months) and stored plasma from PLHIV with incident TB, identified within a South African (SA) and US cohort. We performed temporal trend and discriminant analyses for proteins, and, to assure clinical relevance, we further compared protein levels at TB diagnosis to interferon-gamma release assay (IGRA; SA) or tuberculin-skin test (TST; US) positive and negative cohort subjects without TB. SA and US exploratory data were analyzed separately. Findings: We identified 15 proteins in the SA (n=30) and 10 in the US (n=24) incident TB subjects which both changed from 2 years prior until time of TB diagnosis after controlling for 10% false discovery rate, and were significantly different at time of TB diagnosis compared to non-TB subjects (p<0.01). Five proteins, CD14, A2GL, NID1, SCTM1, and A1AG1, overlapped between both cohorts. Furthermore, after cross-validation, panels of 5 – 12 proteins were able to predict TB up to two years before diagnosis. Interpretation: Host proteins can be biomarkers for increasing Mycobacterium tuberculosis infection activity/burden, incipient TB, and predict TB development in PLHIV. Funding: NIH/NIAID AI117927, AI146329, and AI127173 to JMA.
