Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis

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.

Immune evasion and provocation by Mycobacterium tuberculosis

“…Approaches to develop rational combinations of HDTs that synergize are needed. Finally, it may seem paradoxical to treat infection by reducing inflammation, but in combination with antibiotics such an approach might improve immune function, reduce tissue injury and enhance drug penetration into granulomatous tissue 183 . Given their role as a permissive niche for M. tuberculosis and their role in immunopathology, neutrophils have also been evaluated as targets of HDTs to reduce lung pathology and M. tuberculosis burden 184 .…”

Characteristics of alveolar macrophages in bronchioalveolar lavage fluids from active tuberculosis patients identified by single-cell RNA sequencing

“…In this study, we performed scRNA-seq analysis to characterize alveolar macrophages from BALF in TB patients and made a comparison of BALF samples with healthy controls. We believe this will help uncover the mechanisms of host defense against M. tuberculosis and in the discovery of novel vaccines or therapeutic targets as there are an increasing number of host-directed interventions which target macrophages [ 21 – 22 ] .…”

Adjunctive inhibition of the integrated stress response pathway accelerates bacterial clearance in a mouse model of tuberculosis

“…A finely tuned concert of pro-and anti-inflammatory responses that is elicited by the host in response to infection contributes to both bacterial containment and persistence within organized host structures called granulomas (2)(3)(4)(5). These responses are principal targets for the development of host-directed therapies (HDT) that aim to refocus immune responses toward a more effective elimination of the infection (6)(7)(8)(9). The granuloma, while forming an immune microenvironment that contains the infection, also provides a safe niche enabling the prolonged survival and ultimate transmission of M.tb.…”