Microenvironments of tuberculous granuloma: advances and opportunities for therapy

Abstract

The hallmark tissue lesions of tuberculosis (TB) are granulomas. These multicellular structures exhibit varying degrees of cellular complexity, are dynamic, and show considerable diversity within and between hosts. Categorization based on gross pathologic features, particularly caseation and necrosis, was historically coined prior to the identification of mycobacteria as the causative agent of TB. More recently, granuloma zonation based on immune cell composition, metabolite abundance, and physical characteristics has gained attention. With the advent of single-cell analyses, distinct microenvironments and cellular ecosystems within TB granulomas have been identified. We summarize the architecture of TB granulomas and highlight their cellular heterogeneity, including cell niches as well as physical factors such as oxygen gradients that modulate lesion fate. We discuss opportunities for therapy, highlighting new models and the power of in silico modeling to unravel granuloma features and trajectories. Understanding the relevance of the granuloma microenvironment to disease pathophysiology will facilitate the development of more effective interventions, such as host-directed therapies for TB.

Keywords: granuloma; host-directed therapy; immunity; spatial biology; tuberculosis.

Figure 1

Tuberculous granuloma microenvironment and host-directed therapies. Granulomas are hallmark lesions of tuberculosis (TB) and exhibit distinct cellular zonation, gradients of gases such as oxygen or carbon monoxide (A, B), nutrients such as amino acids and glucose, and various metabolites (C). (D-F) Distinct cellular ecosystems have been identified in TB granulomas. These are defined by polarized macrophages and T-cell immune responses, distinct features of immune cells including transformed macrophages, and cell clusters with distinct spatial positioning. (G) Approaches for host-directed therapies (HDTs) targeting granuloma biology include modulation of inflammation, tissue matrix, and neovascularization. Ala, alanine; Arg, arginine; CBS, cystathionine β-synthase; CO, carbon monoxide; H₂S, hydrogen sulfide; Glu, glucose; HIF, hypoxia-inducible factor; HO-1, hemeoxygenase-1; IDO, indoleamine dioxygenase; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; Mφ, macrophage; MMP, matrix metalloprotease; NO, nitric oxide; PDE, phosphodiesterase; PD-L1, programmed cell death ligand 1; PGE, prostaglandin; T, T-cell; Th, T-helper cell; TNF, tumor necrosis factor; Trp, tryptophan; VEGF, vascular endothelial growth factor. Figure created with Biorender.