Spatial mapping reveals granuloma diversity and histopathological superstructure in human tuberculosis

Abstract

The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping individual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

A protective role for type I interferon signaling following infection with Mycobacterium tuberculosis carrying the rifampicin drug resistance-conferring RpoB mutation H445Y

“…Future experiments could also test whether myeloid cells directly infected with Mtb are type I IFN producers and how the kinetics of infection influences the kinetics of IFN production found in this study [ 48 , 49 ]. Additional insights can also be gained by utilizing newly emerging technologies such as spatial transcriptomics, to study localization of the IFN-producing cell types with respect to infected and other responding cell types [ 50 – 52 ].…”

Agent-based model predicts that layered structure and 3D movement work synergistically to reduce bacterial load in 3D in vitro models of tuberculosis granuloma

“…(43) Multiplex immunofluorescence was recently used to look at the distribution of macrophages, T cells, and B cells in tissue. (44) Individual cells were mapped permitting complex spatial analysis, allowing the defining of lesion types, and showing a diverse spectrum of lesion composition. (44) CD68+ cells were closest to the core of necrotic lesions, followed by CD8+ T cells.…”

“…(44) Individual cells were mapped permitting complex spatial analysis, allowing the defining of lesion types, and showing a diverse spectrum of lesion composition. (44) CD68+ cells were closest to the core of necrotic lesions, followed by CD8+ T cells. In combination with the peripheral location of STAT1 phosphorylation, this suggests colocalization of CD8+ T cells and STAT1 activated macrophages, mirroring our prediction.…”

The role of ESAT-6 in tuberculosis immunopathology

“…Necrosis contributes to cellular injury and emerges from the formation of tuberculous granulomas, organized aggregates of macrophages recruited to contain the infection but also contributes to patient morbidity and Mtb dissemination ( 105 ), mainly through the manifestation of lung lesions. Of note, both non-necrotizing and necrotizing lesions cooperate to form an inflammatory superstructure that determines local immune responses ( 106 ). ESAT-6, particularly through the ESX-1 secretion system, promotes granuloma formation and the recruitment of macrophages to the infectious site ( 107 ).…”