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Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics

Lipoarabinomannan (LAM), an amphiphilic lipoglycan of the Mycobacterium tuberculosis cell wall, is a diagnostic target for tuberculosis. Previous work from our laboratory and others suggests that LAM is associated with host serum lipoproteins, which may in turn have implications for diagnostic assay...

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Autores principales: Jakhar, Shailja, Sakamuri, Ramamurthy, Vu, Dung, Dighe, Priya, Stromberg, Loreen R., Lilley, Laura, Hengartner, Nicolas, Swanson, Basil I., Moreau, Emmanuel, Dorman, Susan E., Mukundan, Harshini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026062/
https://www.ncbi.nlm.nih.gov/pubmed/33826643
http://dx.doi.org/10.1371/journal.pone.0243337
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author Jakhar, Shailja
Sakamuri, Ramamurthy
Vu, Dung
Dighe, Priya
Stromberg, Loreen R.
Lilley, Laura
Hengartner, Nicolas
Swanson, Basil I.
Moreau, Emmanuel
Dorman, Susan E.
Mukundan, Harshini
author_facet Jakhar, Shailja
Sakamuri, Ramamurthy
Vu, Dung
Dighe, Priya
Stromberg, Loreen R.
Lilley, Laura
Hengartner, Nicolas
Swanson, Basil I.
Moreau, Emmanuel
Dorman, Susan E.
Mukundan, Harshini
author_sort Jakhar, Shailja
collection PubMed
description Lipoarabinomannan (LAM), an amphiphilic lipoglycan of the Mycobacterium tuberculosis cell wall, is a diagnostic target for tuberculosis. Previous work from our laboratory and others suggests that LAM is associated with host serum lipoproteins, which may in turn have implications for diagnostic assays. Our team has developed two serum assays for amphiphile detection: lipoprotein capture and membrane insertion. The lipoprotein capture assay relies on capture of the host lipoproteins, exploiting the biological association of host lipoprotein with microbial amphiphilic biomarkers to “concentrate” LAM. In contrast, the membrane insertion assay is independent of the association between pathogen amphiphiles and host lipoprotein association, and directly captures LAM based on its thermodynamic propensity for association with a supported lipid membrane, which forms the functional surface of an optical biosensor. In this manuscript, we explored the use of these assays for the detection of LAM in sera from adults whose tuberculosis status had been well-characterized using conventional microbiological tests, and endemic controls. Using the lipoprotein capture assay, LAM signal/noise ratios were >1.0 in 29/35 (83%) individuals with culture-confirmed active tuberculosis, 8/13 (62%) individuals with tuberculosis symptoms, but no positive culture for M. tuberculosis, and 0/6 (0%) symptom-free endemic controls. To evaluate serum LAM levels without bias associated with potential differences in circulating host lipoprotein concentrations between individuals, we subsequently processed available samples to liberate LAM from associated host lipoprotein assemblies followed by direct detection of the pathogen biomarker using the membrane insertion approach. Using the membrane insertion assay, signal/noise for detection of serum LAM was greater than that observed using the lipoprotein capture method for culture-confirmed TB patients (6/6), yet remained negative for controls (2/2). Taken together, these results suggest that detection of serum LAM is a promising TB diagnostic approach, but that further work is required to optimize assay performance and to decipher the implications of LAM/host lipoprotein associations for diagnostic assay performance and TB pathogenesis.
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spelling pubmed-80260622021-04-15 Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics Jakhar, Shailja Sakamuri, Ramamurthy Vu, Dung Dighe, Priya Stromberg, Loreen R. Lilley, Laura Hengartner, Nicolas Swanson, Basil I. Moreau, Emmanuel Dorman, Susan E. Mukundan, Harshini PLoS One Research Article Lipoarabinomannan (LAM), an amphiphilic lipoglycan of the Mycobacterium tuberculosis cell wall, is a diagnostic target for tuberculosis. Previous work from our laboratory and others suggests that LAM is associated with host serum lipoproteins, which may in turn have implications for diagnostic assays. Our team has developed two serum assays for amphiphile detection: lipoprotein capture and membrane insertion. The lipoprotein capture assay relies on capture of the host lipoproteins, exploiting the biological association of host lipoprotein with microbial amphiphilic biomarkers to “concentrate” LAM. In contrast, the membrane insertion assay is independent of the association between pathogen amphiphiles and host lipoprotein association, and directly captures LAM based on its thermodynamic propensity for association with a supported lipid membrane, which forms the functional surface of an optical biosensor. In this manuscript, we explored the use of these assays for the detection of LAM in sera from adults whose tuberculosis status had been well-characterized using conventional microbiological tests, and endemic controls. Using the lipoprotein capture assay, LAM signal/noise ratios were >1.0 in 29/35 (83%) individuals with culture-confirmed active tuberculosis, 8/13 (62%) individuals with tuberculosis symptoms, but no positive culture for M. tuberculosis, and 0/6 (0%) symptom-free endemic controls. To evaluate serum LAM levels without bias associated with potential differences in circulating host lipoprotein concentrations between individuals, we subsequently processed available samples to liberate LAM from associated host lipoprotein assemblies followed by direct detection of the pathogen biomarker using the membrane insertion approach. Using the membrane insertion assay, signal/noise for detection of serum LAM was greater than that observed using the lipoprotein capture method for culture-confirmed TB patients (6/6), yet remained negative for controls (2/2). Taken together, these results suggest that detection of serum LAM is a promising TB diagnostic approach, but that further work is required to optimize assay performance and to decipher the implications of LAM/host lipoprotein associations for diagnostic assay performance and TB pathogenesis. Public Library of Science 2021-04-07 /pmc/articles/PMC8026062/ /pubmed/33826643 http://dx.doi.org/10.1371/journal.pone.0243337 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Jakhar, Shailja
Sakamuri, Ramamurthy
Vu, Dung
Dighe, Priya
Stromberg, Loreen R.
Lilley, Laura
Hengartner, Nicolas
Swanson, Basil I.
Moreau, Emmanuel
Dorman, Susan E.
Mukundan, Harshini
Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title_full Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title_fullStr Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title_full_unstemmed Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title_short Interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: Implications for blood-based diagnostics
title_sort interaction of amphiphilic lipoarabinomannan with host carrier lipoproteins in tuberculosis patients: implications for blood-based diagnostics
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026062/
https://www.ncbi.nlm.nih.gov/pubmed/33826643
http://dx.doi.org/10.1371/journal.pone.0243337
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