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

Moreira-Teixeira, L and Tabone, O and Graham, C M and Singhania, A and Stavropoulos, E and Redford, P S and Chakravarty, P and Priestnall, S L and Suarez-Bonnet, A and Herbert, E and Mayer-Barber, K D and Sher, A and Fonseca, K L and Sousa, J and Cá, B and Verma, R and Haldar, P and Saraiva, M and O’Garra, A (2020) Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis. Nature Immunology, 21 (4). pp. 464-476. ISSN 1529-2908

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Abstract

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (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 TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.