Genome-wide characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice

We sought to develop and characterize a novel paucibacillary model in mice, which develop necrotic lung granulomas following infection with Mycobacterium tuberculosis. Paucibacillary infection was established, recapitulating the sterilizing activities of human LTBI regimens. TNF neutralization led to increased lung bacillary load, disrupted granuloma architecture with expanded necrotic foci and reduced tissue hypoxia, and accelerated animal mortality. TNF-neutralized mouse lungs and sera showed significant upregulation of IFNγ, IL-1β, IL-6, IL-10, CCL2, CCL3, and matrix metalloproteinase genes Six weeks after aerosol-immunization with recombinant M. bovis BCG overexpressing the 30-kilodalton antigen, C3HeB/FeJ mice were aerosol-infected with M. tuberculosis H37Rv. Six weeks later, mice were treated with one of three standard regimens for latent TB infection (LTBI) or TNF-neutralizing antibody. Mouse lungs were analyzed by histology, positron emission tomography/computed tomography, whole-genome microarrays, and RT-PCR. Lungs and sera were studied by multiplex enzyme-linked immunosorbent assays