title: Macrophage polarization drives granuloma outcome during Mycobacterium tuberculosis infection.
abstract: 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-κB signal activation intervals. These results suggest that the dynamics of NF-κB signaling is a viable therapeutic target to promote M1 polarization early during infection and to improve outcome.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Simeone
authors.initials: S
authors.lastname: Marino
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Cilfone
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mattila
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA kirschne@umich.edu.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004195:Disease Models, Animal; D006099:Granuloma / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008252:Macaca fascicularis; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D016328:NF-kappa B / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology
chemical_list: D016328:NF-kappa B