RESUMEN
UNLABELLED: Latent tuberculosis infection affects one third of the world's population and can reactivate (relapse) decades later. However, current technologies, dependent on postmortem analyses, cannot follow the temporal evolution of disease. METHODS: C3HeB/FeJ mice, which develop necrotic and hypoxic tuberculosis lesions, were aerosol-infected with Mycobacterium tuberculosis. PET and CT were used to serially image the same cohort of infected mice through pretreatment, tuberculosis treatment, and subsequent development of relapse. RESULTS: A novel diffeomorphic registration was successfully used to monitor the spatial evolution of individual pulmonary lesions. Although most lesions during relapse developed in the same regions as those noted during pretreatment, several lesions also arose de novo within regions with no prior lesions. CONCLUSION: This study presents a novel model that simulates infection and reactivation disease as seen in humans and could prove valuable to study tuberculosis pathogenesis and evaluate novel therapeutics.
Asunto(s)
Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Tuberculosis Pulmonar/diagnóstico por imagen , Animales , Antituberculosos/farmacología , Modelos Animales de Enfermedad , Femenino , Pulmón/diagnóstico por imagen , Ratones , Ratones Endogámicos C3H , Mycobacterium tuberculosis , Radiofármacos/farmacología , Recurrencia , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Increased expression of translocator protein (TSPO) is a feature of microglial and macrophage activation. Since activated macrophages are key components of tuberculosis-associated inflammation, we evaluated radioiodinated DPA-713, a synthetic ligand of TSPO, for in vivo imaging of host response. METHODS: Mice were infected with aerosolized Mycobacterium tuberculosis and evaluated using whole-body [(125)I]iodo-DPA-713 single-photon emission computed tomography (SPECT). Ex vivo biodistribution and correlative immunofluorescence studies were also performed. RESULTS: [(125)I]Iodo-DPA-713 SPECT imaging clearly delineated tuberculosis-associated pulmonary inflammation in live animals. Biodistribution studies confirmed radiotracer specificity for inflamed pulmonary tissues. Immunofluorescence studies demonstrated that TSPO is highly expressed in CD68(+) macrophages and phagocytic cells within tuberculosis lesions and that [(125)I]DPA-713 specifically accumulates within these cells. Coadministration of excess unlabelled DPA-713 abrogated both the SPECT and ex vivo fluorescence signals. Lesion-specific signal-to-noise ratios were significantly higher with [(125)I]iodo-DPA-713 SPECT (4.06 ± 0.52) versus [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) (2.00 ± 0.28) performed in the same mice (P = .004). CONCLUSIONS: [(125)I]Iodo-DPA-713 accumulates specifically in tuberculosis-associated inflammatory lesions by selective retention within macrophages and phagocytic cells. [(125)I]Iodo-DPA-713 SPECT provides higher lesion-specific signal-to-noise ratios than [(18)F]FDG PET and may prove to be a more specific biomarker to monitor tuberculosis in situ.