PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis

• DOI: 10.1371/journal.ppat.1005739
• Publication Date: 2016-07-05T17:40:54Z
• Authors: Philana Ling Lin; Pauline Maiello; Hannah P. Gideon; M. Teresa Coleman; Anthony M. Cadena; Mark A. Rodgers; Robert Gregg; Melanie O’Malley; Jaime Tomko; Daniel Fillmore; L. James Frye; Tara Rutledge; Robert M. DiFazio; Christopher Janssen; Edwin Klein; Peter L. Andersen; Sarah M. Fortune; JoAnne L. Flynn
• Keywords: 0301 basic medicine; Physiology; Monkeys; Polymerase Chain Reaction; Diagnostic Radiology; White Blood Cells; Animal Cells; Immune Physiology; Positron Emission Tomography Computed Tomography; Medicine and Health Sciences; Image Processing, Computer-Assisted; Biology (General); Tomography; Mammals; Innate Immune System; T Cells; Radiology and Imaging; Flow Cytometry; Virus Latency; 3. Good health; Actinobacteria; Vertebrates; Granulomas; Cytokines; Cellular Types; Anatomy; Macaque; Research Article; Primates; Imaging Techniques; QH301-705.5; Immune Cells; Immunology; 610; Neuroimaging; Lymphatic System; 03 medical and health sciences; Diagnostic Medicine; Latent Tuberculosis; Old World monkeys; 616; Animals; Blood Cells; Biology and life sciences; Bacteria; Organisms; Cell Biology; Mycobacterium tuberculosis; Molecular Development; RC581-607; Computed Axial Tomography; Disease Models, Animal; Macaca fascicularis; Immune System; Amniotes; Virus Activation; Lymph Nodes; Immunologic diseases. Allergy; Mycobacterium Tuberculosis; Positron Emission Tomography; Developmental Biology; Neuroscience

Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection.