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.
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Data availability
All data are available in the main text, Extended Data figures or the Supplementary Information.
Change history
16 April 2020
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
We thank the Stanley and Cox laboratories for discussions and for support with Mtb experiments, L. Flores, P. Dietzen and R. Chavez for technical assistance, and H. Nolla, A. Valeros and the Cancer Research Laboratory for flow cytometry. We thank the Barton laboratory, I. Rauch, A. Sandstrom, D. Kotov and P. Mitchell for helpful discussions and technical support. We thank B. Penn for comments on the manuscript. Generation of the anti-IL-1Ra antibody was supported by the Extramural Collaborative Research Program of the Cancer Research Institute, Kanazawa University. K.H.D. and R.E.V. were supported by Investigator in the Pathogenesis of Infectious Diseases awards from the Burroughs Wellcome Fund. R.E.V. is an HHMI Investigator and is supported by NIH grants AI075039 and AI066302.
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Contributions
R.E.V., K.H.D. and D.X.J. designed the experiments. L.H.Y. assisted with experiments shown in Fig. 4 and Extended Data Fig. 5. K.J.C. assisted with experiments shown in Extended Data Fig. 3. D.X.J. performed all other experiments. R.E.V. and D.X.J. analysed the data. I.K. generated the B6.Sst1S mice. N.M. generated the anti-IL-1Ra antibody. K.H.D. and I.K. gave technical support and conceptual advice. R.E.V. and D.X.J. prepared the manuscript.
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R.E.V has a financial relationship with Aduro Biotech and both he and the company may benefit from commercialization of the results of this research. All other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 B6.Sst1S BMMs overexpress Ifnb and ISGs when stimulated with TNFα.
a, b, Expression of Ifnb (a) or selected ISGs (b) in BMMs measured by RT-qPCR. Results normalized to housekeeping genes. Representative data of at least two independent experiments.
Extended Data Fig. 2 B6.Sst1SStinggt/gt partially rescues the enhance susceptibility of B6.Sst1S mice to Mtb.
Mice were infected with Mtb and measured for lung bacterial burdens at day 25 (a) or survival (b). a, combined results of 2 experiments. Sample size n (B6, B6.Sst1S, B6.Sst1SStinggt/gt) = 11, 11, 12 (a); 11, 11, 11 (b). All animals except 5 of the B6 were bred in-house (a) and all except B6 were bred in-house (b). Center and error bars show mean and SEM. Analyzed with two-ended Mann–Whitney test (a) or two-ended Log-rank test (b). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
Extended Data Fig. 3 Enhanced inflammation in B6.Sst1S mice requires type I IFN.
a, b, e, f, Protein levels of IL-10 (a), IFNγ (b), TNF (e), and CXCL1 (f) were measured in lungs of Mtb-infected mice at day 25. Combined results of at least three independent infections (a, b, e, f). c, Lung bacterial burden of Mtb-infected mice at day 25 (representative of two independent infections). Input dose: average 100 CFU/mouse. d, CFU corresponding to Fig. 2a and b. Combined results that include those already shown in Figs. 1c, 2c, and Extended Data 3a. Input dose: 10–89 CFU per mouse. g, Neutrophils (CD11b+Ly6G+) from lungs of Mtb-infected mice were enumerated on day 14 and day 25. Combined results of two independent infections. All animals except B6 were bred in-house (a–f); all animals were bred in-house (g). Sample size n (B6, B6.Sst1S, B6.Sst1SIfnar–/–) = 16, 18, 16 (a); 40, 45, 32 (b); 40, 44, 32 (d); 25, 29, 16 (e); 28, 30, 26 (f); 6 for all genotypes (c); 9 for all genotypes (g). Center and error bars show mean and SEM. Analyzed with two-ended Mann–Whitney test (a–g). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
Extended Data Fig. 4 IL-1 blockade increases susceptibility in both B6 and B6.Sst1S mice.
a–c, mice were infected with average 15 CFU/mouse and were treated with anti-IL1R1 or isotype control antibodies, and on day 25 the lungs were measured for bacterial burden (a), IL- 1Ra protein levels (b), and IL-1 bioactivity (c). Sample size n (in order shown, from left) = 7, 7, 8, 8 (a); 7, 8, 9, 8 (b-c). d, Mice were infected with average 78 CFU/mouse and IL-1 bioactivity was measured in the lungs at day 25. n = 5 for both samples. e, Mice were infected with average 33 CFU/mouse. IL-1 bioactivity was measured in lung samples collected on the indicated days. n = 6 for all samples except day 36 B6.Sst1S = 4. Day 25 data already shown in Fig. 3d. All animals except B6 were bred in-house (a–c); all were bred in-house (d-e). Center and error bars show mean and SEM. Analyzed with two-ended Mann–Whitney test (a–c). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
Extended Data Fig. 5 Homozygous or heterozygous Il1rn deletion protects B6.Sst1S mice from Mtb infection.
a, Body weights on day 28 of individual mice shown in Fig. 4c. b-c, Mice were infected with Mtb at average 17 CFU/mouse (b) or 60 CFU/mouse (c), and at day 21 lungs were harvested to measure IL-1 bioactivity. d, RT-qPCR on lungs of Mtb-infected mice, sampled at 25 days post-infection. Each graph combined results from 2 independent experiments. e-f, Mice infected with average 20 CFU/mouse were treated with either anti-IL-1R1 antibody or isotype control every 3 days starting 7 days post-infection (e), or anti-IL-1Ra antibody or PBS control every other day starting 3 days post-infection (f). At 25 days post-infection lungs were harvested for measuring bacterial burden. Sample size n (from left as shown) = 11, 12, 22, 10 (a); 6, 8, 11 (b); 6, 8, 10 (c); 11, 14, 11, 5(d); 5, 6, 3, 4, 2, 3 (e); 8, 8, 6, 6 (f). All mice were bred in-house (a, d–f) or all except B6 were bred in-house (b-c); and all except B6 and B6.Sst1S were littermates (a, d, e). Center and error bars show mean and SEM. Analyzed with two-ended Mann–Whitney test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
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Ji, D.X., Yamashiro, L.H., Chen, K.J. et al. Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra. Nat Microbiol 4, 2128–2135 (2019). https://doi.org/10.1038/s41564-019-0578-3
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DOI: https://doi.org/10.1038/s41564-019-0578-3
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