Quantification of Circulating Mtb Antigens for Rapid TB Diagnosis and Treatment Monitoring
Abstract
The proposed study will develop and refine a rapid, point-of-care, and inexpensive diagnostic tool that can sensitively diagnose active tuberculosis (TB), the leading cause of death from infectious disease. There are an estimated 10.4 million new TB cases and 1.7 million TB-related deaths per year, and developing countries bear >90% of the global TB burden. Current approaches have proven unsuccessful in controlling this disease, and global efforts have repeatedly failed to achieve goals set by the World Health Organization, United Nations and other multinational organizations. The health threat posed by the global TB epidemic is made even worse by the increased frequency of drug-resistant TB cases, which has almost doubled since 2010. TB is considered to be among the most dangerous health threats to military men and women deployed to overseas battlefields and humanitarian missions. Time-consuming culture tests are still commonly used for TB diagnosis and to identify drug-resistant TB cases in much of the world. These cultures commonly require weeks to provide a final result and are unable to detect some types of TB disease, and the delay associated with these methods can delay the decision to start and to end treatment. More advanced assays can reduce the time required for TB diagnosis, but do not work well on many forms of TB and are not useful in monitoring responses to therapy. A rapid, easy-to-use, and reliable diagnostic platform is therefore highly needed to allow rapid TB diagnosis and treatment of military forces in harsh environmental conditions, such as war zones. Sputum, gastric lavage, or invasive biopsy samples (e.g., cerebral spinal fluid) samples are required to perform most standard TB assays, but these specimens have multiple limitations. For example, sputum can be difficult to obtain from some subjects, especially as their symptoms resolve under treatment and may not be useful in subjects who have disease that is not localized to the lungs (e.g., tuberculous meningitis). Diagnosis of TB disease outside of the lungs may require that biopsies be taken from multiple different sites. Mycobacterium tuberculosis (Mtb), the pathogen responsible for TB, secretes several factors required for it to maintain an active infection. These factors can accumulate in most body fluids, including blood, making them excellent markers for the diagnosis of active TB cases. A blood-based assay that recognizes these factors would be ideal for diagnosing active TB disease, but these factors can be masked by interactions with abundant proteins present in blood and there are currently no assays that reliably detect these factors in patient samples to diagnose active TB disease. We recently developed a nanoparticle-based approach to address the issues associated with detection of Mtb-derived factors in human blood samples. This diagnostic platform can rapidly and sensitively detect and quantitate TB antigen levels directly from blood samples and provides quantitative results to allow prompt diagnosis and rapid evaluation of a patient’s response to treatment. Our approach employs porous silicon NanoDisks that increase antigen capture efficiency from blood and the absorbance and transfer of UV (ultraviolet) laser energy to increase the detection of these captured peptides by mass spectrometry. This approach has several advantages: (1) It uses a small non-infectious blood sample, rather than a sputum or an invasive biopsy sample that contains live Mtb bacilli and that can be highly variable. (2) It has high sensitivity and specificity for all active TB disease, including in patients that exhibit low levels of Mtb bacilli in conventional samples (paucibacillary TB cases), which includes culture-negative, HIV-infected, and pediatric TB cases. (3) It directly quantifies Mtb-derived factors to allow rapid monitoring of the magnitude of the infection and its response to treatment. (4) It employs a streamlined approac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910026
Entities
People
- Ye Hu
Organizations
- Tulane University of Louisiana
- United States Army