Barbara Killy

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B6 Reprogramming of macrophages by the mycobacterial cord factor

Principal investigator
Roland Lang

Mentor
Stefan Wirtz

The role of miRNAs in the cord factor mediated inhibition of IFNγ-induced gene expression in murine macrophages

Tuberculosis remains the leading cause of death as a result of a single bacterial agent, infecting about one third of the world’s population. The causative agent Mycobacterium tuberculosis (MTB), a gram-positive, facultative intracellular bacterium, developed very successful strategies to subvert detection of the host immune system. It succeeds to survive and replicate in macrophages by blocking phagosomal maturation and at least in part through inhibition of IFNγ-induced antimicrobial responses. The molecular mechanisms underlying these survival strategies are still unclear. 
The most abundant glycolipid in the cell wall of virulent mycobacteria is trehalose-6,6-dimycolate (TDM), also known as cord factor. It is recognized by the C-type lectin receptor Mincle and activates an intracellular signaling cascade involving FcRγ, Syk and Card9.
Extensive transcriptome microarray analysis revealed both synergistic and antagonistic effects of TDM on IFNγ-stimulated gene expression in murine macrophages, suggesting that TDM mediates at least to some extent inhibitory effects of mycobacteria on IFNγ signaling.
In this project, we aim to ascertain whether microRNAs (miRNAs) are involved in TDM-mediated negative regulation. Using miRNA microarray technologies we will identify changes in host miRNA levels caused by TDM. Potential target genes of these miRNAs will be predicted and their role in the impairment of IFNγ-induced responses will be analyzed in further detail. With this approach, we hope to provide a better understanding of how TDM reprograms host macrophages.

Figure: TDM-mediated inhibition of IFNγ responses in murine macrophages. Putative model how the mycobacterial cord factor changes host microRNA expression via Mincle-Syk-Card9 signaling pathway in order to impair IFN γ-induced antimicrobial gene expression.

 

Publications

 

Presentations

October 2016 8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany
”Dual role of the mycobacterial Cord factor TDM in cross-regulation of macrophage response to IFNg”
Poster
     
March 2016 20. Symposium "Infektionen und Immunabwehr", Burg Rothenfels, Germany
”microRNAs in the Cord factor mediated inhibition of IFN gamma induced gene expression”
Talk
     
October 2015 2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
”The Role of miRNAs in the Cord factor mediated inhibition of IFN gamma induced gene expression in murine macrophages”
Poster
     
September 2015 66. Jahrestagung der Deutschen Gesellschaft für Hygiene und Mikrobiologie DGHM, Münster, Germany
”The Role of microRNAs in the Cord factor mediated inhibition of IFN gamma induced gene expression in murine macrophages”
Poster
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”The role of microRNAs in the cord factor mediated inhibition of IFN-γ-induced gene expression”
Poster