title: Biomarkers for Tuberculosis Based on Secreted, Species-Specific, Bacterial Small Molecules.
abstract: Improved biomarkers are needed for tuberculosis. To develop tests based on products secreted by tubercle bacilli that are strictly associated with viability, we evaluated 3 bacterial-derived, species-specific, small molecules as biomarkers: 2 mycobactin siderophores and tuberculosinyladenosine. Using liquid chromatography-tandem mass spectrometry, we demonstrated the presence of 1 or both mycobactins and/or tuberculosinyladenosine in serum and whole lung tissues from infected mice and sputum, cerebrospinal fluid (CSF), or lymph nodes from infected patients but not uninfected controls. Detection of the target molecules distinguished host infection status in 100% of mice with both serum and lung as the target sample. In human subjects, we evaluated detection of the bacterial small molecules (BSMs) in multiple body compartments in 3 patient cohorts corresponding to different forms of tuberculosis. We detected at least 1 of the 3 molecules in 90%, 71%, and 40% of tuberculosis patients' sputum, CSF, and lymph node samples, respectively. In paucibacillary forms of human tuberculosis, which are difficult to diagnose even with culture, detection of 1 or more BSM was rapid and compared favorably to polymerase chain reaction-based detection. Secreted BSMs, detectable in serum, warrant further investigation as a means for diagnosis and therapeutic monitoring in patients with tuberculosis.
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Pan
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa San Francisco School of Medicine, University of California, Oakland Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Asa
authors.initials: A
authors.lastname: Tapley
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Tessa
authors.initials: T
authors.lastname: Little
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Urbanowski
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors.forename: Keira
authors.initials: K
authors.lastname: Cohen
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pym
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Deepak
authors.initials: D
authors.lastname: Almeida
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Afton
authors.initials: A
authors.lastname: Dorasamy
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Emilie
authors.initials: E
authors.lastname: Layre
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: David C
authors.initials: DC
authors.lastname: Young
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine.
authors.forename: Ravesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Neurology, University of KwaZulu Natal.
authors.forename: Vinod B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Tuberculosis & HIV Investigative Network in KwaZulu-Natal (THINK), Durban, South Africa.
authors.forename: Kristina
authors.initials: K
authors.lastname: Wallengren
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine Max Planck Institute for Infection Biology, Berlin, Germany Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: Department of Medicine, Edendale Hospital, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
authors.forename: Douglas
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Bishai
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000032:analysis; D000818:Animals; D015373:Bacterial Typing Techniques; D015415:Biomarkers / Q000032:analysis*; D002853:Chromatography, Liquid; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000302:isolation & purification; D010080:Oxazoles / Q000032:analysis*; D013183:Sputum / Q000382:microbiology; D053719:Tandem Mass Spectrometry; D014376:Tuberculosis / Q000175:diagnosis*
chemical_list: D015415:Biomarkers; D010080:Oxazoles; C018608:mycobactins; D000241:Adenosine
keywords: biomarker; diagnostic; mycobactin; small molecule; tuberculosinyladenosine; tuberculosis