title: Computational modeling predicts IL-10 control of lesion sterilization by balancing early host immunity-mediated antimicrobial responses with caseation during mycobacterium tuberculosis infection.
abstract: Although almost a third of the world's population is infected with the bacterial pathogen Mycobacterium tuberculosis, our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine IL-10 at the level of the granuloma has proven difficult because of lesional heterogeneity and the limitations of animal models. In this study, we take an in silico approach and, through a series of virtual experiments, we predict several novel roles for IL-10 in tuberculosis granulomas: 1) decreased levels of IL-10 lead to increased numbers of sterile lesions, but at the cost of early increased caseation; 2) small increases in early antimicrobial activity cause this increased lesion sterility; 3) IL-10 produced by activated macrophages is a major mediator of early antimicrobial activity and early host-induced caseation; and 4) increasing levels of infected macrophage derived IL-10 promotes bacterial persistence by limiting the early antimicrobial response and preventing lesion sterilization. Our findings, currently only accessible using an in silico approach, suggest that IL-10 at the individual granuloma scale is a critical regulator of lesion outcome. These predictions suggest IL-10-related mechanisms that could be used as adjunctive therapies during tuberculosis.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Cilfone
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Ford
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Simeone
authors.initials: S
authors.lastname: Marino
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mattila
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.
authors.forename: Hannah P
authors.initials: HP
authors.lastname: Gideon
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109; linderma@umich.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
mesh_terms: D000818:Animals; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology*
chemical_list: C508609:IL10 protein, human; D016753:Interleukin-10