<i>Mycobacterium tuberculosis</i>Decreases Human Macrophage IFN-γ Responsiveness through miR-132 and miR-26a

Ni, Bin; Rajaram, Murugesan V. S.; Lafuse, William P.; Landes, Michelle B.; Schlesinger, Larry S.

doi:10.4049/jimmunol.1400124

Cited by 92 publications

(69 citation statements)

References 37 publications

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“…Regulation of miRNA upon Mtb infections is an intense area of investigation. Several studies in the past have shown specific miRNA expression upon Mtb infection [34–38]. It is therefore very likely that the cell could have evolved the APA strategy to counter the miRNA-mediated decay in the infected macrophages as well.…”

Section: Introductionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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Transcriptional reprogramming of macrophages upon Mycobacterium tuberculosis (Mtb) infection is widely studied; however, the significance of alternate splicing (AS) in shaping cellular responses to mycobacterial infections is not yet appreciated. Alternate splicing can influence transcript stability or structure, function and localization of corresponding proteins thereby altering protein stoichiometry and physiological consequences. Using comprehensive analysis of a time-series RNA-seq data obtained from human macrophages infected with virulent or avirulent strains of Mtb, we show extensive remodeling of alternate splicing in macrophage transcriptome. The global nature of this regulation was evident since genes belonging to functional classes like trafficking, immune response, autophagy, redox and metabolism showed marked departure in the pattern of splicing in the infected macrophages. The systemic perturbation of splicing machinery in the infected macrophages was apparent as genes involved at different stages of spliceosome assembly were also regulated at the splicing level. Curiously there was a considerable increase in the expression of truncated/non-translatable variants of several genes, specifically upon virulent infections. Increased expression of truncated transcripts correlated with a decline in the corresponding protein levels. We verified the physiological relevance for one such candidate gene RAB8B; whose truncated variant gets enriched in H37Rv infected cells. Upon tweaking relative abundance of longer or shorter variants of RAB8B transcripts by specialized transduction, mycobacterial targeting to lysosomes could be promoted or blocked respectively, which also resulted in corresponding changes in the bacterial survival. Our results show RAB8B recruitment to the mycobacterial phagosomes is required for phagosome maturation. Thus the abundance of truncated RAB8B variant helps virulent Mtb survival by limiting the RAB8B levels in the cells, a mechanism which we subsequently verified in human primary macrophages. Taken together we demonstrate alternate splicing as a new locus of intervention by Mtb and provide attractive alternative to exploit for novel drug targets against Mtb.

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Section: Introductionmentioning

confidence: 99%

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

2017

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“…These two microRNAs share a seed sequence and therefore target many of the same genes. Several groups have demonstrated that Mirc19 is an important regulator of immune function (Lagos et al, 2010; Nakahama et al, 2013; Ni et al, 2014; Shaked et al, 2009). We now show that Mirc19 plays a critical role in maintaining the balance between function and survival of aged HSCs.…”

Section: Introductionmentioning

confidence: 99%

The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression

et al. 2015

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Summary MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is up-regulated during aging. Both over-expression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrates that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that may play a role in age-related hematopoietic defects.

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“…For instance, secreted effectors from Salmonella stimulate, via the p53 signalling pathway, the expression of miR-128, which targets the macrophage colonystimulating factor (M-CSF) and thereby leads to impaired M-CSF-mediated macrophage recruitment [83]. Likewise, M. tuberculosis can limit macrophage response to IFN-γ by up-regulating miR-132 and miR-26a [84]. These two miRNAs down-regulate the transcriptional coactivator p300, a component of the IFN-γ signalling cascade.…”

Section: Manipulation Of Cell Physiologymentioning

confidence: 99%

Mammalian microRNAs and long noncoding RNAs in the host-bacterial pathogen crosstalk

Duval

Cossart

Lebreton

2017

Seminars in Cell & Developmental Biology

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Gene expression regulation is a critical question in host-pathogen interactions, and RNAs act as key players in this process. In this review, we focus on the mammalian RNA response to bacterial infection, with a special interest on microRNAs and long non-coding RNAs. We discuss the role of cellular miRNAs in immunity, the implication of circulating miRNAs as well as the influence of the microbiome on the miRNA response. We also review how pathogens counteract the host miRNA expression. Interestingly, bacterial non-coding RNAs regulate host gene expression and conversely eukaryotic miRNAs may regulate bacterial gene expression. Overall, the characterization of RNA regulatory networks represents an emerging theme in the field of host pathogen interactions.

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Mycobacterium tuberculosisDecreases Human Macrophage IFN-γ Responsiveness through miR-132 and miR-26a

Cited by 92 publications

References 37 publications

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression

Mammalian microRNAs and long noncoding RNAs in the host-bacterial pathogen crosstalk

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