1. Cytoplasmic RNA Sensor Pathways and Nitazoxanide Broadly Inhibit Intracellular Mycobacterium tuberculosis Growth
- Author
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Aya Nambu, Veit Hornung, Gail H. Cassell, Anne E. Goldfeld, Thomas S. Ebert, Supriya Sadhukhan, Viraga Haridas, Shahin Ranjbar, Luke D. Jasenosky, and James V. Falvo
- Subjects
0301 basic medicine ,Immunology ,chemical and pharmacologic phenomena ,02 engineering and technology ,Biology ,Microbiology ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,Gene expression ,Sense (molecular biology) ,lcsh:Science ,Immune Response ,Multidisciplinary ,Innate immune system ,Signal transducing adaptor protein ,RNA ,Molecular Microbiology ,MDA5 ,Biological Sciences ,biochemical phenomena, metabolism, and nutrition ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Protein kinase R ,Cell biology ,030104 developmental biology ,lcsh:Q ,0210 nano-technology - Abstract
Summary To establish stable infection, Mycobacterium tuberculosis (MTb) must overcome host innate immune mechanisms, including those that sense pathogen-derived nucleic acids. Here, we show that the host cytosolic RNA sensing molecules RIG-I-like receptor (RLR) signaling proteins RIG-I and MDA5, their common adaptor protein MAVS, and the RNA-dependent kinase PKR each independently inhibit MTb growth in human cells. Furthermore, we show that MTb broadly stimulates RIG-I, MDA5, MAVS, and PKR gene expression and their biological activities. We also show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits intracellular MTb growth and amplifies MTb-stimulated RNA sensor gene expression and activity. This study establishes prototypic cytoplasmic RNA sensors as innate restriction factors for MTb growth in human cells and it shows that targeting this pathway is a potential host-directed approach to treat tuberculosis disease., Graphical Abstract, Highlights • MTb infection induces RNA sensor (RIG-I, MDA5, PKR) mRNA levels and activities • RIG-I, MDA5, MAVS, and PKR restrict intracellular MTb growth in human cells • NTZ enhances MTb-driven RNA sensor mRNA levels and RLR activities • NTZ and NTZ derivatives inhibit intracellular MTb growth in primary human cells, Biological Sciences; Immunology; Immune Response; Microbiology; Molecular Microbiology
- Published
- 2019