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Gene expression analysis of WT, IFNAR KO, or STING KO bone marrow derived macrophages treated with IFNbeta and/or infected with live or heat killed Mycobacterium tuberculosis

ABSTRACT: The aim of this study was to identify the signaling pathways differentially engaged upon infection with either live or heat killed Mycobacterium tuberculosis in murine bone marrow derived macrophages. Based on preliminary data that type I IFN signaling dominates the transcriptional differences, we investigated what roles the type I IFN receptor IFNAR and the signaling molecule STING play during infection with either live or heat killed Mycobacterium tuberculosis in bone marrow derived macrophages. In WT and STING KO macrophages, IFNbeta treatment was added either by itself or in addition to both of the infection conditions to test whether the lack of IFNbeta induction in these cells accounted for any differences in transcriptional respones.added IFNbeta treatment either by itself or in addition to both of the infection conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE162620 | GEO | 2021/03/29

REPOSITORIES: GEO

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Project description:Phagocytosis requires the activation of a plethora of mechanisms that include the activation of the actin cytoskeleton guided by the Arp2/3 complex. These are promoted by activators such as the Wiskott Aldrich Syndrome Protein (WASP) family members. In order to further understand the molecular mechanisms involved in the early events leading the phagocytosis of the pathogenic Mycobacterium tuberculosis, we set out to examine potential roles of miRNAs in phagocytosis using genome-wide expression profiling to identify miRNAs differentially regulated following mycobacterial infection. One of the miRNAs activated upon infection of mouse macrophages with the non-pathogenic Mycobacterium smegmatis, the widely conserved miR-142-3p, was predicted and confirmed to target the Neural-WASP (N-WASP). Upregulating of miR-142-3p in mouse macrophages inversely correlated with levels of N-WASP, upon infection with live pathogenic and non-pathogenic mycobacteria, suggesting an active role of Mycobacterium tuberculosis on the regulation of phagocytosis, at the post-transcriptional level, in host cells. The reduction of N-WASP correlated with a reduced internalization of bacteria per macrophage, independently of the phagocytosis index. Furthermore, the downregulation of WASP levels accompanied those of N-WASP, at early but not at late time points, suggesting a closely regulatory mechanism among both family members, dependent on the time frame of the phagocytosis. Additionally, upregulating of miR-142-3p promoted the change in the protein levels of another predicted and confirmed target, the Cofilin2 protein, in a phagocytosis-independent fashion. Downregulation experiments promoted aberrant morphologic phenotypes in macrophages, similar to observed by others in PBMCs of humans with Wiskott Aldrich Syndrome, suggesting the strong involvement of miR-142-3p on the regulation of the actin machinery in macrophages. Altogether these results show for the first time that miRNAs are involved in the regulation of actin-mediated phagocytosis of pathogenic bacteria and that these are direct targets of Mycobacterium tuberculosis. Expression analysis of mouse macrophage cell line J774A.1 in response to infection with Mycobacterium smegmatis mc2155 EGFP. Three biological replicates each for uninfected and infected samples.

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Gene expression analysis of WT, IFNAR KO, or STING KO bone marrow derived macrophages treated with IFNbeta and/or infected with live or heat killed Mycobacterium tuberculosis

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