A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination

• Published in: PLoS computational biology Vol. 16; no. 5; p. e1007280
• Main Authors: Wessler, Timothy, Joslyn, Louis R, Borish, H Jacob, Gideon, Hannah P, Flynn, JoAnne L, Kirschner, Denise E, Linderman, Jennifer J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.05.2020; Public Library of Science (PLoS)
• Subjects: Authorship; Bacteria; BASIC BIOLOGICAL SCIENCES; Biology and Life Sciences; CD8 antigen; Chemical engineering; Computational biology; Computer applications; Cytokines; cytotoxic T cells; Development and progression; Funding; Granuloma; Granulomas; Immune system; Immunology; Infections; Laboratory animals; Lungs; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; macaque; Macrophages; MATHEMATICS AND COMPUTING; Medicine; Medicine and Health Sciences; Methods; Mycobacterium tuberculosis; Ordinary differential equations; pulmonary imaging; Pulmonary tuberculosis; Research and Analysis Methods; Software; Supervision; T cells; Tuberculosis; United States; Pittsburgh Pennsylvania; Ann Arbor Michigan; United States > US; Pennsylvania; Michigan
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1007280

Mycobacterium tuberculosis (Mtb), the causative infectious agent of tuberculosis (TB), kills more individuals per year than any other infectious agent. Granulomas, the hallmark of Mtb infection, are complex structures that form in lungs, composed of immune cells surrounding bacteria, infected cells, and a caseous necrotic core. While granulomas serve to physically contain and immunologically restrain bacteria growth, some granulomas are unable to control Mtb growth, leading to bacteria and infected cells leaving the granuloma and disseminating, either resulting in additional granuloma formation (local or non-local) or spread to airways or lymph nodes. Dissemination is associated with development of active TB. It is challenging to experimentally address specific mechanisms driving dissemination from TB lung granulomas. Herein, we develop a novel hybrid multi-scale computational model, MultiGran, that tracks Mtb infection within multiple granulomas in an entire lung. MultiGran follows cells, cytokines, and bacterial populations within each lung granuloma throughout the course of infection and is calibrated to multiple non-human primate (NHP) cellular, granuloma, and whole-lung datasets. We show that MultiGran can recapitulate patterns of in vivo local and non-local dissemination, predict likelihood of dissemination, and predict a crucial role for multifunctional CD8+ T cells and macrophage dynamics for preventing dissemination.