title: Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing.
abstract: Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only ∼5-10% will develop clinical disease. Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb. Active disease occurs in ∼45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic. Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB.
authors: 1] Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. [2].
authors: Philana Ling
authors: PL
authors: Lin
authors: 1] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3].
authors: Christopher B
authors: CB
authors: Ford
authors: Department of Radiology, Positron Emission Tomography Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: M Teresa
authors: MT
authors: Coleman
authors: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Amy J
authors: AJ
authors: Myers
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Richa
authors: R
authors: Gawande
authors: Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, USA.
authors: Thomas
authors: T
authors: Ioerger
authors: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USA.
authors: James
authors: J
authors: Sacchettini
authors: 1] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA.
authors: Sarah M
authors: SM
authors: Fortune
authors: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: JoAnne L
authors: JL
authors: Flynn
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D018450:Disease Progression; D006099:Granuloma / Q000276:immunology / Q000382:microbiology; D007538:Isoniazid; D055985:Latent Tuberculosis / Q000382:microbiology*; D008168:Lung / Q000382:microbiology; D008252:Macaca fascicularis; D008954:Models, Biological; D009169:Mycobacterium tuberculosis; D011157:Population Dynamics; D049268:Positron-Emission Tomography; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology* / Q000517:prevention & control
chemical_list: D007538:Isoniazid