Abstract
Globally, more than 10 million people developed active tuberculosis (TB), with 1.4 million deaths in 2020. In addition, the emergence of drug-resistant strains in many regions of the world threatens national TB control programs. This requires an understanding of host-pathogen interactions and finding novel treatments including host-directed therapies (HDTs) is of utter importance to tackle the TB epidemic. Mycobacterium tuberculosis (Mtb), the causative agent for TB, mainly infects the lungs causing inflammatory processes leading to immune activation and the development and formation of granulomas. During TB disease progression, the mononuclear inflammatory cell infiltrates which form the central structure of granulomas undergo cellular changes to form epithelioid cells, multinucleated giant cells and foamy macrophages. Granulomas further contain neutrophils, NK cells, dendritic cells and an outer layer composed of T and B lymphocytes and fibroblasts. This complex granulomatous host response can be modulated by Mtb to induce pathological changes damaging host lung tissues ultimately benefiting the persistence and survival of Mtb within host macrophages. The development of cavities is likely to enhance inter-host transmission and caseum could facilitate the dissemination of Mtb to other organs inducing disease progression. This review explores host targets and molecular pathways in the inflammatory granuloma host immune response that may be beneficial as target candidates for HDTs against TB.
Highlights
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB)
We previously reported in mice that statins reduced Mtb burden by enhancing autophagy, phagosome maturation and decreasing pulmonary pathology with fewer and smaller lesion sizes [30], suggesting a role for statins as host-directed drug therapies (HDTs) in TB [164]
Persistent pulmonary inflammation and ongoing paucibacillary Mtb replication have moved into the focus of adjunctive HDT research [175,176,177,178,179,180,181]
Summary
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB). After COVID-19, TB remains the second leading cause of death from a single infectious agent with an estimated 1.4 million global deaths in 2020 [1]. People with TB disease are subjected to long treatment durations and drug side effects often lead to poor adherence, increasing the risk of developing drug-resistance. Targeting host factors has emerged as novel TB treatment approaches termed host-directed drug therapies (HDTs). Mtb infection leads to host inflammatory responses which enhances the destruction of the lung tissues causing pulmonary lesions and pathogen replication sites. The identification of pulmonary host targets for HDTs will aim to limit immune pathological lung destruction and increase host immune responses to control Mtb proliferation and persistence. The formation of granulomas in the lungs is a prominent hallmark during TB disease progression and is originally believed to provide a host-protective cellular structure to contain Mtb infection. Targeting host factors that can influence the tuberculous granuloma could become an effective HDT approach for TB. We focused on HDTs that were evaluated in preclinical animal models or ex vivo granuloma models to reduce granulomatous lesions and ameliorate pulmonary inflammatory tissue pathology
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