Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra
- 14 October 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Microbiology
- Vol. 4 (12), 2128-2135
- https://doi.org/10.1038/s41564-019-0578-3
Abstract
The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen1. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response2,3,4,5,6,7. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models6,7,8,9,10,11. Here, we examined B6.Sst1S congenic mice that carry the ‘susceptible’ allele of the Sst1 locus that results in exacerbated Mtb disease12,13,14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections6,7,15,16,17,18. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1S mice. Our results illustrate the value of the B6.Sst1S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI075039, AI066302)
This publication has 71 references indexed in Scilit:
- The sst1 Resistance Locus Regulates Evasion of Type I Interferon Signaling by Chlamydia pneumoniae as a Disease Tolerance MechanismPLoS Pathogens, 2013
- Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause MortalityPLOS ONE, 2013
- Mycobacterium Tuberculosis Activates the DNA-Dependent Cytosolic Surveillance Pathway within MacrophagesCell Host & Microbe, 2012
- Innate and Adaptive Interferons Suppress IL-1α and IL-1β Production by Distinct Pulmonary Myeloid Subsets during Mycobacterium tuberculosis InfectionImmunity, 2011
- TheN-Ethyl-N-Nitrosourea-InducedGoldenticketMouse Mutant Reveals an Essential Function ofStingin theIn VivoInterferon Response toListeria monocytogenesand Cyclic DinucleotidesInfection and Immunity, 2011
- Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritisAnnals Of The Rheumatic Diseases, 2011
- An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosisNature, 2010
- Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage populationJCI Insight, 2010
- Induction of IFN-αβ enables Listeria monocytogenes to suppress macrophage activation by IFN-γThe Journal of Experimental Medicine, 2010
- 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A productionProceedings of the National Academy of Sciences of the United States of America, 2009