Exploring the Interaction of Amphiphilic Mycobacterial Lipoarabinomannan with Lipoproteins: Implications for Blood Based Diagnosis
Currently, over one-third of the global population is infected with tuberculosis (TB), one of the world’s most deadly infectious diseases. The current gold standard for TB diagnosis is microbiological culture, which can take up to 6-8 weeks, which is not conducive to timely treatment. There are no reliable diagnostics for TB. Disease manifestation and outcome of diagnostic tests for TB is influenced by co-morbidities such as HIV co-infection, further complicating diagnostics development. Thus, there is a need for reliable diagnostics for TB. This is especially true in pediatric populations where the differential disease presentation further complicates outcomes. This dissertation describes the development and evaluation of new tailored methods-lipoprotein capture and membrane insertion- for the discriminative detection of an amphiphilic mycobacterial biomarker, lipoarabinomannan (LAM), for diagnosis of TB in adult and pediatric populations. LAM is released by Mycobacterium tuberculosis during active infection and associates with serum lipoproteins such as high and low density lipoproteins (HDL/LDL) in the human host. The guiding hypothesis of this work is that the vi sequestration of LAM in immune complexes and by lipoprotein carriers in the host contributes to difficulty in detection of the amphiphilic antigen in blood. To this end, we have evaluated the use of tailored amphiphile detection assays to process and measure sequestered LAM in host blood, and examined the application of this methodology in adults and children with TB disease. In addition, we have developed and studied an in vitro cell model to further extrapolate the impact of association of LAM with host carriers on its ability to induce innate immune processes, in order to better refine and design strategies for its direct detection. Overall, our conclusions indicate that the amphiphilic biochemistry of LAM and its interaction with lipoproteins is a feature which should be taken into account for the effective development of diagnostics.
- Research Organization:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Univ. of New Mexico, Albuquerque, NM (United States)
- Sponsoring Organization:
- USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program
- DOE Contract Number:
- 89233218CNA000001
- OSTI ID:
- 1784691
- Report Number(s):
- LA-UR-21-25029
- Country of Publication:
- United States
- Language:
- English
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