Outcome of Mycobacterium tuberculosis infection in humans is clinically defined as "active" or "latent". These clinical definitions are inadequate to describe the continuum of M. tuberculosis infection. The actual presentation of "active" tuberculosis varies from mild to severe pulmonary disease, including cavitary tuberculosis, and to extrapulmonary or disseminated disease. Several lines of evidence support that latent infection is also a spectrum of infection outcomes, from subclinical disease to "dormant infection" to completely cleared infection. The concept of a latency spectrum has practical implications: we hypothesize that only a small percentage of latently infected persons is most likely to reactive TB, and identifying those persons, who we believe are "higher" on the latency spectrum, allows one to target interventions to those who most will benefit. In this proposal, we will explore the concept of the spectrum of latency and implications for reactivation using a systems biology approach. We propose to integrate data from humans, non-human primates, and computational systems to provide a comprehensive approach to latency and reactivation. We will use immunologic methods and state-of-the-art imaging technology to define the spectrum of latency in humans and non-human primates infected with M. tuberculosis. From non-human primates, we will go one step further and obtain granulomas for detailed study of the spectrum of latency, as well as during reactivation. These granulomas will be used in immunologic, microbiologic and pathologic studies to identify which are most likely to reactivate and the factors involved in maintaining a subclinical infection. In addition to vastly increasing our understanding of "latent" TB and the factors that contribute to reactivation, all of the human and non-human primate data will be incorporated into next generation multi-scale mathematical models of tuberculosis. This will provide the computational platform for sophisticated analysis of factors that contribute to the spectrum of latency and the risk of reactivation. Ultimately these models, informed by data from humans and a very relevant animal model, can be used to test our hypothesis that the position of an individual on the spectrum of latency influences the risk of reactivation. This project brings together an experienced team of immunologists, microbiologists, and computational scientists who have focused on the study of tuberculosis for many years.

Public Health Relevance

Mycobacterium tuberculosis, the causative agent of tuberculosis, can cause clinically apparent disease (TB) or more commonly a clinically silent infection (latent TB) that can reactivate to cause TB as well. It is estimated that 1.7 billion people worldwide have latent TB infection. Here we integrate data from humans and animal models with computational and mathematical models in a comprehensive systems biology approach to a better understanding of latent TB and the factors that lead to reactivation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106804-04
Application #
8527829
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (S1))
Program Officer
Peavy, Hannah H
Project Start
2010-09-17
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$614,716
Indirect Cost
$98,201
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Lin, Philana Ling; Ford, Christopher B; Coleman, M Teresa et al. (2014) Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 20:75-9
Guzzetta, Giorgio; Kirschner, Denise (2013) The roles of immune memory and aging in protective immunity and endogenous reactivation of tuberculosis. PLoS One 8:e60425
Kozakiewicz, Lee; Phuah, Jiayao; Flynn, Joanne et al. (2013) The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. Adv Exp Med Biol 783:225-50
Mattila, Joshua T; Ojo, Olabisi O; Kepka-Lenhart, Diane et al. (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191:773-84
Gong, Chang; Mattila, Joshua T; Miller, Mark et al. (2013) Predicting lymph node output efficiency using systems biology. J Theor Biol 335:169-84
El-Kebir, M; van der Kuip, M; van Furth, A M et al. (2013) Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-*. J Theor Biol 328:43-53
Myers, Amy J; Marino, Simeone; Kirschner, Denise E et al. (2013) Inoculation dose of Mycobacterium tuberculosis does not influence priming of T cell responses in lymph nodes. J Immunol 190:4707-16
Fallahi-Sichani, Mohammad; Flynn, JoAnne L; Linderman, Jennifer J et al. (2012) Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability. J Immunol 188:3169-78

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