Uncloaking an ancient adversary: Can pathogen biomarker elicitors play a role in confirming extrapulmonary TB and latent TB infection?

Latent tuberculosis infection (LTBI) is diagnosed immunologically using the Mantoux tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). While widely used, immunodiagnostics can produce false negative or false positive results. Pathogen biomarkers provide an alternative, but direct detection in LTBI and extrapulmonary TB cases is challenging. Mycobacterium tuberculosis grows slowly, has limited hematogenous movement, is protected by a lipid rich cell wall, and produces low levels of secreted factors. Here we discuss the potential of elicitors by first considering pathogen markers that may be released following the administration of isoniazid. Isoniazid targets the cell wall of mycobacteria found in extracellular compartments and within monocytes, macrophages, dendritic cells, and lymphatic endothelial cells. Isoniazid's dual-purpose potential as an antibiotic and elicitor is supported by knowledge of latent infection dynamics, time-kill kinetics, and new detection techniques. Within hours, the bactericidal action of isoniazid likely enriches plasma with M. tuberculosis DNA, RNA, proteins/peptides, and lipids. Undoubtedly a portion of these biomarkers are eliminated as some bacilli undergo phagocytosis and lysosomal destruction. However, advances in immunoprecipitation and nucleic acid amplification, combined with the use of larger blood volumes during assay development, may overcome these losses. Other anticipated challenges include determining optimal sample collection times and designing diagnostic workflows that minimize processing-associated marker loss and degradation. Conventional, commercial, and emerging technologies that address these variables are discussed. If realized, isoniazid associated markers could provide proof of concept for novel elicitor-based diagnostic approaches capable of confirming LTBI and empirically treated extrapulmonary TB.