Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages

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.

Activating transcription factor 3 modulates the macrophage immune response toMycobacterium tuberculosisinfection via reciprocal regulation of inflammatory genes and lipid body formation

“…Previous reports have shown that EGR1 regulates ATF3 expression in murine αT3-1 cells (Mayer, Dexheimer, Nishida, Kitajima, & Thiel, 2008). Both we and others have observed through global transcriptome profiling that challenge of macrophages with M. tuberculosis leads to an early upregulation of EGR1 (Kumar et al, 2015;Roy et al, 2018). In this study, we validated the early upregulation of EGR1 transcript in infected RAW264.7 ( Figure 2a) and BMDMs ( Figure 2b).…”

“…It is ubiquitously expressed and is induced upon challenge of a variety of cell types by bacteria (de Klerk, Saroj, Wassing, Maudsdotter, & Jonsson, 2017). Both we and others have observed through global transcriptome profiling that challenge of macrophages with M. tuberculosis leads to an early upregulation of EGR1 (Kumar et al, 2015;Roy et al, 2018). Both we and others have observed through global transcriptome profiling that challenge of macrophages with M. tuberculosis leads to an early upregulation of EGR1 (Kumar et al, 2015;Roy et al, 2018).…”

Analysis of cellular and soluble profiles in QuantiFERON nonconverters, converters, and reverters in the Gambia

“…It is thought that Th2 cytokines such as IL-13 can cause inappropriate activation of macrophages and thus, undermine the Th1 response suitable for an intracellular pathogen like Mtb. 21 We also found increased levels of IL-17A, IP-10 and MIP1β in converters compared with nonconverters. IL-17A is associated with Th17 responses with a previous study from our laboratory showing contrasting findings (ie, increased IL-17A in TBR).…”

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…In the later stages and chronic disease, the infection is associated with responses mediated by M2 macrophages, whose weak microbicidal activity and ability to eliminate bacteria are linked to the occurrence of the lesions observed during disease evolution. [265][266][267][268][269] In leprosy, macrophages are the primary cells that exert microbicidal activity. Thus, the role of macrophages in the response to M. leprae has been widely described and is correlated with the expression of certain cytokines that are classical representatives of the cellular immune response, such as TNF-α and IFN-γ.…”