Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human TB resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human tuberculosis disease, with a dominance of a type I IFN response and neutrophil activation and recruitment, together with a loss in B lymphocyte, NK and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B, NK and T cell effector responses in the lung upon infection. Importantly, the blood signature of active disease shared by mice and humans is also evident in latent tuberculosis progressors before diagnosis suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.