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Title: Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics

Abstract

Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of ‘monomeric’ LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. Furthermore, this phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilicmore » in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host–pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics.« less

Authors:
 [1];  [1];  [2];  [2];  [3];  [3];  [1];  [1]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. International Tuberculosis Research Center, Changwon (Republic of Korea)
  3. National Inst. of Allergy and Infectious Diseases, Bethesda, MD (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1235738
Report Number(s):
LA-UR-14-28713
Journal ID: ISSN 1472-9792; PII: S1472979213000383
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Tuberculosis
Additional Journal Information:
Journal Volume: 93; Journal Issue: 3; Journal ID: ISSN 1472-9792
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; pediatric tuberculosis; biosurveillance; diagnostics

Citation Formats

Sakamuri, Rama Murthy, Price, Dominique N., Lee, Myungsun, Cho, Sang Nae, Barry, Clifton E., Via, Laura E., Swanson, Basil I., and Mukundan, Harshini. Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics. United States: N. p., 2013. Web. doi:10.1016/j.tube.2013.02.015.
Sakamuri, Rama Murthy, Price, Dominique N., Lee, Myungsun, Cho, Sang Nae, Barry, Clifton E., Via, Laura E., Swanson, Basil I., & Mukundan, Harshini. Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics. United States. doi:10.1016/j.tube.2013.02.015.
Sakamuri, Rama Murthy, Price, Dominique N., Lee, Myungsun, Cho, Sang Nae, Barry, Clifton E., Via, Laura E., Swanson, Basil I., and Mukundan, Harshini. Thu . "Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics". United States. doi:10.1016/j.tube.2013.02.015. https://www.osti.gov/servlets/purl/1235738.
@article{osti_1235738,
title = {Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics},
author = {Sakamuri, Rama Murthy and Price, Dominique N. and Lee, Myungsun and Cho, Sang Nae and Barry, Clifton E. and Via, Laura E. and Swanson, Basil I. and Mukundan, Harshini},
abstractNote = {Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of ‘monomeric’ LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. Furthermore, this phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host–pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics.},
doi = {10.1016/j.tube.2013.02.015},
journal = {Tuberculosis},
number = 3,
volume = 93,
place = {United States},
year = {2013},
month = {2}
}

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