Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Abstract

c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

“…IL-10 is an antiinflammatory cytokine that inhibits formation of mature granulomas [37]. A T H 1 to T H 2 shift has long been considered characteristic of HIV-associated immune dysregulation [38], tending to impair granuloma formation [10][11][12]. Further, increased ARG1 expression limits Tcell proliferation, independent of its effect on NO [10].…”

“…Among persons with HIV infection, granuloma formation is impaired. Unlike immunocompetent persons, in whom granulomas display a finely organized architecture with spatially modulated gradients of T-cell and macrophage phenotypes [10][11][12], patients with tuberculosis with advanced HIV infection develop disorganized granulomas that are poorly contained collections of polymorphonuclear cells and eosinophils with a paucity of mononuclear, epithelioid, or giant cells [13][14][15][16][17]. Poorly contained lesions in animal tissues are not hypoxic, and this may also be the case in HIV-infected patients with tuberculosis [8,9,18,19].…”

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

“…ESAT-6, a secreted virulence factor not expressed by the attenuated vaccine strain, M. bovis BCG, up-regulated MMP-10 secretion, implicating this pathway in mycobacterial pathology. Furthermore, increased MMP-10 expression has been shown to drive macrophage polarization toward an M2-like phenotype (20), an alternatively activated form of macrophage that is present within TB granulomas and associated with Mtb persistence (38).…”

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

“…At the molecular level, the model accounts for secretion, diffusion, binding, and degradation of cytokines and chemokines. The model has been extensively calibrated to NHP data and successfully predicts granuloma outcomes for tumor necrosis factor alpha (TNF-␣), interleukin-10 (IL-10), and IFN-␥ knockouts (34)(35)(36)(37)(38)(39)(40)(41)61).…”