Spatial and temporal evolution of lung granulomas in a cynomolgus macaque model of Mycobacterium tuberculosis infection

Abstract

BackgroundLittle is known about granuloma progression of Mycobacterium tuberculosis infection in humans. Using serial positron emission tomography and computed tomography (PET/CT) of an animal model that recapitulates human infection with M. tuberculosis, we are able to track lung granulomas. ObjectiveWe characterized the spatial and temporal pattern of granuloma formation during primary infection and reactivation. MethodsSerial PET/CT was performed on cynomolgus macaques (n = 28) during primary and reactivation M. tuberculosis infection. Distances between granulomas during the first six weeks post infection (“primary” granulomas) were compared to new granulomas that developed afterwards (“secondary” granulomas) using nearest neighbor analysis during primary infection, reactivation and between different routes of infection. ResultsSecondary granulomas developed within 2 cm of a primary granuloma within the same lung lobe with 80% probability during the course of primary infection, and this same pattern was observed during reactivation of latent infection after immune suppression. Using a logistic growth function, we were able to predict the maximum number of granulomas that would develop over the course of infection with good correlation (R2 = 0.96). ConclusionThese data provide important insights into the dynamic patterns of bacterial dissemination during the earliest phases of primary infection and reactivation tuberculosis.