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.

Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.

BackgroundHuman Endogenous Retroviruses (HERVs) and Mammalian apparent LTR-retrotransposons (MaLRs) represent the 8% of our genome and are distributed among our 46 chromosomes. These LTR-retrotransposons are thought to be essentially silent except in cancer, autoimmunity and placental development. Their Long Terminal Repeats (LTRs) constitute putative promoter or polyA regulatory sequences. In this study, we used a recently described high-density microarray which can be used to study HERV/MaLR transcriptome including 353,994 HERV/MaLR loci and 1559 immunity-related genes.ResultsWe described, for the first time, the HERV transcriptome in peripheral blood mononuclear cells (PBMCs) using a cellular model mimicking inflammatory response and monocyte anergy observed after septic shock. About 5.6% of the HERV/MaLR repertoire is transcribed in PBMCs. Roughly one-tenth [5.7–13.1%] of LTRs exhibit a putative constitutive promoter or polyA function while one-quarter [19.5–27.6%] may shift from silent to active. Evidence was given that some HERVs/MaLRs and genes may share similar regulation control under lipopolysaccharide (LPS) stimulation conditions. Stimulus-dependent response confirms that HERV expression is tightly regulated in PBMCs. Altogether, these observations make it possible to integrate 62 HERVs/MaLRs and 26 genes in 11 canonical pathways and suggest a link between HERV expression and immune response. The transcriptional modulation of HERVs located close to genes such as OAS2/3 and IFI44/IFI44L or at a great distance from genes was discussed.ConclusionThis microarray-based approach revealed the expression of about 47,466 distinct HERV loci and identified 951 putative promoter LTRs and 744 putative polyA LTRs in PBMCs. HERV/MaLR expression was shown to be tightly modulated under several stimuli including high-dose and low-dose LPS and Interferon-γ (IFN-γ). HERV incorporation at the crossroads of immune response pathways paves the way for further functional studies and analyses of the HERV transcriptome in altered immune responses in vivo such as in sepsis.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4901-9) contains supplementary material, which is available to authorized users.