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

Abstract

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.

Transfer transcriptomic signatures for infectious diseases

“…Transfer learning also uses information from larger compendia of datasets to inform and constrain the models. Our work and that of others also support the possibility of extending prediction across species; for example, a recent study indicates that the mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis (38). The approach also found significant information content in more general sets of signatures, such as those listed in the hallmark gene sets of the Molecular Signatures Database, a result consistent with recent observations (39) and the use of co-expression patterns to define transcriptome modules (40).…”

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

“…2a ). Myeloid and granulocyte-associated modules HB3, HB5, HB8, HB14 and HB23 previously described as over-abundant in the blood from TB patients 35 and mouse models of increased susceptibility to TB 16 , showed increased over-abundance in the blood from infected mice treated with αGM-CSF (Fig. 2a ), shown quantitatively by Eigengene expression (Fig.…”

“…To gain insight into the changes in gene expression caused by GM-CSF blockade during M. tuberculosis infection, we tested our previously reported blood modular TB signature, which distinguishes TB patients from healthy controls 35 and is recapitulated in TB-susceptible strains of mice 16 , on our blood RNA-Seq data from infected and uninfected αGM-CSF versus Ctrl Ab treated mice (Supplementary Data 3 and Fig. 2a ).…”

“…Consistently, studies in mouse models of TB demonstrated that induction of high and sustained levels of type I IFN by different mechanisms result in increased host susceptibility to M. tuberculosis infection 7 , 10 – 15 . Transcriptomic analyses in human and mouse studies have also revealed an over-abundance of type I IFN and granulocyte-associated genes correlating with lung disease severity in both active TB patients and TB-susceptible mice 16 . In humans, neutrophils are the predominant cell type infected with M. tuberculosis in the airways and are detected within inflammatory lung lesions of patients with active disease 17 , 18 .…”

Lung gene expression signatures suggest pathogenic links and molecular markers for pulmonary tuberculosis, adenocarcinoma and sarcoidosis

“…Previous studies on blood transcriptional profiling of TB patients have provided enlightening insights into TB immunopathogenesis and diagnosis [17][18][19] . However, blood-based immunodiagnostic tests are inevitably influenced by the change of global host immune status 20 .…”