期刊
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
卷 3, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcimb.2013.00019
关键词
phagocytosis; N-Wasp; miRNA; miR-142-3p; tuberculosis; macrophage; M. tuberculosis; M. smegmatis
资金
- Portuguese Funding Agency, Fundacao para a Ciencia e Tecnologia (FCT) [PTDC/BIA-BCM/102123/2008, PTDC/SAU-MII/098024/2008, PIC/82859/2007]
- CNRS
- ERANET/ERASysBio grant TB-Host-Net
- Fondation pourla Recherche Medicale
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-BCM/102123/2008, PTDC/SAU-MII/098024/2008] Funding Source: FCT
Mycobacterium tuberculosis (Mtb) is a successful intracellular pathogen that thrives in macrophages (M phi s). There is a need to better understand how Mtb alters cellular processes like phagolysosome biogenesis, a classical determinant of its pathogenesis. A central feature of this bacteria's strategy is the manipulation of M phi actin. Here, we examined the role of microRNAs (miRNAs) as a potential mechanism in the regulation of actin-mediated events leading to phagocytosis in the context of mycobacteria infection. Given that non-virulent Mycobacterium smegmatis also controls actin filament assembly to prolong its intracellular survival inside host cells, we performed a global transcriptomic analysis to assess the modulation of miRNAs upon M. smegmatis infection of the murine M phi cell line, J774A.1. This approach identified miR-142-3p as a key candidate to be involved in the regulation of actin dynamics required in phagocytosis. We unequivocally demonstrate that miR-142-3p targets N-Wasp, an actin-binding protein required during microbial challenge. A gain-of-function approach for miR-142-3p revealed a down-regulation of N-Wasp expression accompanied by a decrease of mycobacteria intake, while a loss-of-function approach yielded the reciprocal increase of the phagocytosis process. Equally important, we show Mtb induces the early expression of miR-142-3p and partially down-regulates N-Wasp protein levels in both the murine J774A.1 cell line and primary human M phi s. As proof of principle, the partial siRNA-mediated knock down of N-Wasp resulted in a decrease of Mtb intake by human M phi s, reflected in lower levels of colony-forming units (CFU) counts over time. We therefore propose the modulation of miRNAs as a novel strategy in mycobacterial infection to control factors involved in actin filament assembly and other early events of phagolysosome biogenesis.
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