Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages

Sugata Roy,Harukazu Suzuki,Bogumil Kaczkowski,Timo Lassmann,Mumin Ozturk,Hideya Kawaji,Vladimir B Bajic,Reto Guler,Piero Carninci,Ousman Tamgue,Suraj P Parihar,Sebastian Schmeier,Tanvir Alam,Yoshihide Hayashizaki,Frank Brombacher,Alistair R R Forrest,Masayoshi Itoh,Erik Arner

doi:10.1038/s41598-018-24509-6

Abstract

Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host-pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNγ (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb-induced differentially expressed genes revealed various terms, related to host-protection and inflammation, enriched in up-regulated genes. On the other hand, terms related to dis-regulation of cellular functions were enriched in down-regulated genes. Differential expression analysis revealed known as well as novel transcription factor genes in Mtb infection, many of them significantly down-regulated. IFNγ or IL-4/IL-13 pre-stimulation induce additional differentially expressed genes in Mtb-infected macrophages. Cluster analysis uncovered significant numbers, prolonging their expressional changes. Furthermore, Mtb infection augmented cytokine-mediated M1 and M2 pre-activations. In addition, we identified unique transcriptional features of Mtb-mediated differentially expressed lncRNAs. In summary we provide a comprehensive in depth gene expression/regulation profile in Mtb-infected macrophages, an important step forward for a better understanding of host-pathogen interaction dynamics in Mtb infection.

Highlights

University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia. 5International
We compared differentially expressed genes of M1- and M2-pre-activated Mycobacterium tuberculosis (Mtb)-infected bone marrow-derived macrophages (BMDMs)’s (IFNγ_Mtb and IL-4/IL-13_Mtb) with those of non-pre-activated Mtb-infected BMDM’s (Fig. 1a, see comparison II), which was designed to explore the differential effects of macrophage M1 and M2 pre-activation in Mtb infection
We comprehensively analyzed the transcriptome of Mtb-infected macrophages and the effect of IFNγ (M1) or IL-4/IL-13 (M2) pre-stimulation in a time-dependent manner using our unique CAGE technology

Summary

Introduction

University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia. 5International. Expressed genes in each condition/time point were compared among M1-and M2-stimulated BMDMs and non-activated Mtb-infected BMDM’s (Fig. 1a, see comparison I).

Results

Conclusion