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

Abstract

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.

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

“…Serial PET-CT imaging using [ 18 F]fluorodeoxyglucose (FDG) as a PET probe is a relatively noninvasive approach that provides insight into the infection process over time. We have used this imaging technology in macaques to assess early events in M. tuberculosis infection, reactivation kinetics, responses to drug treatment and vaccination, and, where possible, compared with human imaging data (16,26,29,30,32,33). Here, we performed serial PET-CT imaging on each macaque in this study to assess similarities and differences among species during infection.…”

“…The extrapulmonary score takes into account the pathology for each organ outside the lung and the number of extrapulmonary samples, including granulomas, that were positive for growth of M. tuberculosis. Surprisingly, some gran-ulomas observed grossly in the liver or spleen do not yield M. tuberculosis CFU (colony-forming units), similar to a subset of granulomas in the lungs (26,32). Using this extrapulmonary scoring system, rhesus macaques had significantly higher extrapulmonary scores than CCM did (median extrapulmonary scores of 16.0 for rhesus macaques and 3.5 for CCM; P ϭ 0.0002); 15/26 (58%) of CCM had extrapulmonary involvement compared to 16/18 (89%) rhesus macaques and 5/6 (83%) of MCM (Fig.…”

“…We use serial positron emission tomography and computed tomography (PET-CT), which combines a functional map (PET) of the thoracic cavity, depending on the PET probe used, with a spatial map of anatomic structures (CT) (29). Using this imaging strategy in our macaques, we can assess drug efficacy in vivo (29,30) and study critical events during infection (26,(31)(32)(33). Comparative genomic studies have been performed for rhesus and cynomolgus macaques and showed that, while abundant heterogeneity exists in each population, there is an extraordinarily high degree of similarity in both species to human genes (34), and there is great similarity in the T cell responses to M. tuberculosis epitopes between both cynomolgus and rhesus macaques and humans (35).…”

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

“…18 F]-fluoro-Dglucose PET/CT scanning to evaluate immune activity in human LTBI (36), as has been reported previously for macaques (27). In any case, however, the characteristics of the two LTBI cohorts being examined in this study must be considered.…”

“…Importantly, both humans and macaques develop a spectrum of latent infection (4,22,26). In the macaque model, the spectrum of LTBI can be distinguished by PET/CT characteristics that are associated with the risk of reactivation (27). Although this range of manifestations is similar to the diverse outcomes of human Mtb infection, cynomolgus macaques are nevertheless more susceptible to Mtb than are humans, in that z50% of infected animals develop active disease within months of initial infection, whereas only 5% of otherwise healthy humans do so.…”