Abstract
ABSTRACTCost-effective animal models that accurately reflect the pathological progression of pulmonary tuberculosis are needed to screen and evaluate novel tuberculosis drugs and drug regimens. Pulmonary disease in humans is characterized by a number of heterogeneous lesion types that reflect differences in cellular composition and organization, extent of encapsulation, and degree of caseous necrosis. C3HeB/FeJ mice have been increasingly used to model tuberculosis infection because they produce hypoxic, well-defined granulomas exhibiting caseous necrosis following aerosol infection with Mycobacterium tuberculosis. A comprehensive histopathological analysis revealed that C3HeB/FeJ mice develop three morphologically distinct lesion types in the lung that differ with respect to cellular composition, degree of immunopathology and control of bacterial replication. Mice displaying predominantly the fulminant necrotizing alveolitis lesion type had significantly higher pulmonary bacterial loads and displayed rapid and severe immunopathology characterized by increased mortality, highlighting the pathological role of an uncontrolled granulocytic response in the lung. Using a highly sensitive novel fluorescent acid-fast stain, we were able to visualize the spatial distribution and location of bacteria within each lesion type. Animal models that better reflect the heterogeneity of lesion types found in humans will permit more realistic modeling of drug penetration into solid caseous necrotic lesions and drug efficacy testing against metabolically distinct bacterial subpopulations. A more thorough understanding of the pathological progression of disease in C3HeB/FeJ mice could facilitate modulation of the immune response to produce the desired pathology, increasing the utility of this animal model.
Highlights
Here, the authors investigate the histopathological response to aerosol infection in the C3HeB/FeJ mouse model, which develops caseous necrotic pulmonary granulomas, a type of lung lesion often seen in humans with TB
Upon histological examination we were able to identify three distinct lesion types by 5 weeks following aerosol infection that differed by cellular composition and organization
We identified three morphologically distinct lesion types present within the lungs of C3HeB/FeJ mice that differed with respect to cellular composition, control of bacterial replication, intracellular versus extracellular location of bacilli, degree of immunopathology, and kinetics of lesion progression
Summary
It has been estimated that approximately one third of the world is infected with Mycobacterium tuberculosis, with the vast majority of these individuals serving as a latently infected asymptomatic. Through the use of 18F-fluorodeoxyglucose positron emission tomography (PET) computed tomography (CT), it has recently become apparent that individual pulmonary lesions can change substantially over time (Barry et al, 2009). These observations have been confirmed and extended using the nonhuman primate model, suggesting that lesions within an individual animal follow independent pathological trajectories and that the sum of these trajectories might best represent disease outcome (Lin et al, 2013, 2014). Nonhuman primates can replicate many of the lesion types and histological features of human disease, the high cost precludes their use for drug screening
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