Biomedical Sciences ETDs

Publication Date

Spring 4-13-2021

Abstract

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 are 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 tuberculosisduring 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 sequestration of LAM in immune complexes and by lipoprotein carriers in the host contributes to difficulty in the detection of the amphiphilic antigen in the 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 vitrocell model to further extrapolate the impact of the association of LAM with host carriers on its ability to induce innate immune processes, 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.

Keywords

Tuberculosis, Diagnostics, Lipoarabinomannan

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Harshini Mukundan

Second Committee Member

Dr. Steven W. Graves

Third Committee Member

Dr. Pavan Muttil

Fourth Committee Member

Dr. Douglas J. Perkins

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