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Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis.

ABSTRACT: AIM:Tuberculosis meningitis (TBM) diagnosis is difficult, new biomarkers are needed. We evaluated the diagnostic utility of delta-like 1 protein (DLL1), vitamin D binding protein (VDBP) and fetuin. METHODS:Biomarker concentrations were measured by ELISA in cryopreserved cerebrospinal fluid from 139 HIV-infected Ugandans with suspected meningitis. TBM was diagnosed by GeneXpert MTB/Rif or culture. Cohort diagnoses included TBM (n = 22), cryptococcal (n = 71), or aseptic meningitis (n = 16) and no meningitis (n = 30). RESULTS:DLL1 (cut-off value 1150 pg/ml) provided 32% sensitivity and 98% specificity. Adding fetuin, cryptococcal antigen and IFN-? resulted in sensitivities of 36, 63 and 76% with specificities of 98, 90 and 92%, respectively. VDBP (cut-off value 2.0 ?g/ml) provided 81% sensitivity and 68% specificity while fetuin (cut-off value 2 ?g/ml) provided a sensitivity of 86% and specificity of 68%. CONCLUSION:CSF DLL1, VDBP and fetuin exhibited fair diagnostic performance for TBM diagnosis.

SUBMITTER: Bahr NC

PROVIDER: S-EPMC6161141 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis.

Bahr Nathan C NC Halupnick Ryan R Linder Grace G Kiggundu Reuben R Nabeta Henry W HW Williams Darlisha A DA Musubire Abdu K AK Morawski Bozena M BM Sreevatsan Srinand S Meya David B DB Rhein Joshua J Boulware David R DR

Biomarkers in medicine 20180601 7

<h4>Aim</h4>Tuberculosis meningitis (TBM) diagnosis is difficult, new biomarkers are needed. We evaluated the diagnostic utility of delta-like 1 protein (DLL1), vitamin D binding protein (VDBP) and fetuin.<h4>Methods</h4>Biomarker concentrations were measured by ELISA in cryopreserved cerebrospinal fluid from 139 HIV-infected Ugandans with suspected meningitis. TBM was diagnosed by GeneXpert MTB/Rif or culture. Cohort diagnoses included TBM (n = 22), cryptococcal (n = 71), or aseptic meningitis ...[more]

PMID: 29856234

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Project description:Rationale: Calcium plays an essential role in the biology of vertebrates. Calcium content in body fluids is maintained within a narrow physiologic range by feedback control. Phosphate is equally important for metabolism and is likewise controlled, albeit over a wider range. This results in a nearly supersaturated state of calcium phosphate in body liquids driving mineral precipitation in soft tissues, which is actively prevented by calcification inhibitors. The hepatic plasma protein fetuin-A is a circulating mineralization inhibitor regulating calcium phosphate crystal growth and calcified matrix metabolism. Ectopic mineralization is associated with many pathological conditions aggravating their outcome. Current diagnostic methods lack sensitivity towards microcalcifications representing the initial stages of the process. Given the irreversibility of established calcifications, novel diagnostic tools capable of detecting nascent calcium phosphate deposits are highly desirable. Methods: We designed fluorescent fusion proteins consisting of fetuin-A coupled to a green or red fluorescent protein derivate, mEmerald or mRuby3, respectively. The proteins were expressed in mammalian cell lines. Sequence optimization resolved folding issues and increased sensitivity of mineral binding. Chimeric proteins were tested for their ability to detect calcifications in cell cultures and tissue sections retrieved from calcification-prone mice. Results: We employed novel genetically labeled fetuin-A-based fluorescent proteins for the detection of ectopic calcifications. We show that fetuin-A-based imaging agents are non-toxic and suitable for live imaging of microcalcifications beyond the detection limit of conventional staining techniques. The ability of fetuin-A to preferentially bind nascent calcium phosphate crystals allowed the resolution of histopathological detail of early kidney damage that went previously undetected. Endogenous expression of fetuin-A fluorescent fusion proteins allowed extended live imaging of calcifying cells with unprecedented sensitivity and specificity. Conclusion: Ectopic microcalcifications represent a major clinical concern lacking effective diagnostic and treatment options. In this paper, we describe novel highly sensitive fetuin-A-based fluorescent probes for imaging microcalcifications. We show that fusion proteins consisting of a fetuin-A mineral binding moiety and a fluorescent protein are superior to the routine methods for detecting calcifications. They also surpass in continuous live cell imaging the chemically fluorescence labeled fetuin-A, which we established previously.

Dataset Information

Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis.

Publications

Delta-like 1 protein, vitamin D binding protein and fetuin for detection of Mycobacterium tuberculosis meningitis.

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