| Summary: | Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. “Multi-omics” approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of “omics” approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of “omics” approaches in host biomarkers innovation and clinical implementation. © 2021 Elsevier GmbH
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