Journal
NATURE MEDICINE
Volume 20, Issue 1, Pages 75-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3412
Keywords
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Funding
- Bill & Melinda Gates Foundation
- Otis Childs Trust of the Children's Hospital of Pittsburgh Foundation
- US National Institutes of Health, National Institute of Allergy and Infectious Diseases DAIT
- US National Institutes of Health [HL106804, AI094745, HL110811, DP2 0D001378, AI076217]
- Howard Hughes Medical Institute, the Physician Scientist Early Career Award
- Harvard Merit Fellowship
- Burroughs Wellcome Foundation Investigator in the Pathogenesis of Infectious Diseases Fellowship
- Robert A. Welch Foundation
- Melvin J. and Geraldine L. Glimcher Associate Professorship
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL106804, R01HL110811] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI007638, R01AI094745, U19AI076217] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP2OD001378] Funding Source: NIH RePORTER
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Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only similar to 5-10% will develop clinical disease(1). 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(2). Active disease occurs in similar to 45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic(2,3). 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.
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