Cytoplasmic RNA Sensor Pathways and Nitazoxanide Broadly Inhibit Intracellular Mycobacterium tuberculosis Growth

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 commo...

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Bibliographic Details
Published iniScience Vol. 22; pp. 299 - 313
Main Authors Ranjbar, Shahin, Haridas, Viraga, Nambu, Aya, Jasenosky, Luke D., Sadhukhan, Supriya, Ebert, Thomas S., Hornung, Veit, Cassell, Gail H., Falvo, James V., Goldfeld, Anne E.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 20.12.2019
Elsevier
Subjects
Biological Sciences
Immune Response
Immunology
Microbiology
Molecular Microbiology
Biological Sciences
Immunology
Microbiology
Immune Response
Molecular Microbiology
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ISSN2589-0042
2589-0042
DOI10.1016/j.isci.2019.11.001

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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. [Display omitted] •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
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Lead Contact
Present address: Profectus Biosciences, Pearl River, NY 10965, USA
These authors contributed equally
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2019.11.001