Skip to main content
Top
Published in: Immunity & Ageing 1/2014

Open Access 01-12-2014 | Short report

Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis

Authors: David E Harrison, Clinton M Astle, M Khalid Khan Niazi, Samuel Major, Gillian L Beamer

Published in: Immunity & Ageing | Issue 1/2014

Login to get access

Abstract

Background

Tuberculosis, the disease due to Mycobacterium tuberculosis, is an important cause of morbidity and mortality in the elderly. Use of mouse models may accelerate insight into the disease and tests of therapies since mice age thirty times faster than humans. However, the majority of TB research relies on inbred mouse strains, and these results might not extrapolate well to the genetically diverse human population. We report here the first tests of M. tuberculosis infection in genetically heterogeneous aging mice, testing if old mice benefit from rapamycin.

Findings

We find that genetically diverse aging mice are much more susceptible than young mice to M. tuberculosis, as are aging human beings. We also find that rapamycin boosts immune responses during primary infection but fails to increase survival.

Conclusions

Genetically diverse mouse models provide a valuable resource to study how age influences responses and susceptibility to pathogens and to test interventions. Additionally, surrogate markers such as immune measures may not predict whether interventions improve survival.
Appendix
Available only for authorised users
Literature
1.
go back to reference Austad SN: Issues in the choice of genetic configuration for animal aging models. Exp Gerontol. 1997, 32 (1–2): 55-63. 10.1016/S0531-5565(96)00033-2.CrossRefPubMed Austad SN: Issues in the choice of genetic configuration for animal aging models. Exp Gerontol. 1997, 32 (1–2): 55-63. 10.1016/S0531-5565(96)00033-2.CrossRefPubMed
3.
go back to reference Svenson KL, Gatti DM, Valdar W, Welsh CE, Cheng R, Chesler EJ, Palmer AA, McMillan L, Churchill GA: High-resolution genetic mapping using the mouse diversity outbred population. Genetics. 2012, 190 (2): 437-447. 10.1534/genetics.111.132597.PubMedCentralCrossRefPubMed Svenson KL, Gatti DM, Valdar W, Welsh CE, Cheng R, Chesler EJ, Palmer AA, McMillan L, Churchill GA: High-resolution genetic mapping using the mouse diversity outbred population. Genetics. 2012, 190 (2): 437-447. 10.1534/genetics.111.132597.PubMedCentralCrossRefPubMed
4.
go back to reference Churchill GA, Gatti DM, Munger SC, Svenson KL: The diversity outbred mouse population. Mamm Genome. 2012, 23 (9–10): 713-718. 10.1007/s00335-012-9414-2.PubMedCentralCrossRefPubMed Churchill GA, Gatti DM, Munger SC, Svenson KL: The diversity outbred mouse population. Mamm Genome. 2012, 23 (9–10): 713-718. 10.1007/s00335-012-9414-2.PubMedCentralCrossRefPubMed
5.
go back to reference Aspinall R: Age-related changes in the function of T cells. Microsc Res Tech. 2003, 62 (6): 508-513. 10.1002/jemt.10412.CrossRefPubMed Aspinall R: Age-related changes in the function of T cells. Microsc Res Tech. 2003, 62 (6): 508-513. 10.1002/jemt.10412.CrossRefPubMed
6.
go back to reference Mori T, Leung CC: Tuberculosis in the global aging population. Infect Dis Clin North Am. 2010, 24 (3): 751-768. 10.1016/j.idc.2010.04.011.CrossRefPubMed Mori T, Leung CC: Tuberculosis in the global aging population. Infect Dis Clin North Am. 2010, 24 (3): 751-768. 10.1016/j.idc.2010.04.011.CrossRefPubMed
7.
go back to reference Fox GJ, Menzies D: Epidemiology of Tuberculosis Immunology. The new Paradigm of Immunity to Tuberculosis, Advances in Experimental Medicine and Biology. Edited by: Divangahi M. 2013, Springer Science+Business Media, New York Fox GJ, Menzies D: Epidemiology of Tuberculosis Immunology. The new Paradigm of Immunity to Tuberculosis, Advances in Experimental Medicine and Biology. Edited by: Divangahi M. 2013, Springer Science+Business Media, New York
8.
go back to reference Orme IM: Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol. 1987, 138 (12): 4414-4418.PubMed Orme IM: Aging and immunity to tuberculosis: increased susceptibility of old mice reflects a decreased capacity to generate mediator T lymphocytes. J Immunol. 1987, 138 (12): 4414-4418.PubMed
9.
go back to reference Cooper AM, Callahan JE, Griffin JP, Roberts AD, Orme IM: Old mice are able to control low-dose aerogenic infections with Mycobacterium tuberculosis. Infect Immun. 1995, 63 (9): 3259-3265.PubMedCentralPubMed Cooper AM, Callahan JE, Griffin JP, Roberts AD, Orme IM: Old mice are able to control low-dose aerogenic infections with Mycobacterium tuberculosis. Infect Immun. 1995, 63 (9): 3259-3265.PubMedCentralPubMed
10.
go back to reference Orme IM, Griffin JP, Roberts AD, Ernst DN: Evidence for a defective accumulation of protective t cells in old mice infected with Mycobacterium tuberculosis. Cell Immunol. 1993, 147 (1): 222-229. 10.1006/cimm.1993.1062.CrossRefPubMed Orme IM, Griffin JP, Roberts AD, Ernst DN: Evidence for a defective accumulation of protective t cells in old mice infected with Mycobacterium tuberculosis. Cell Immunol. 1993, 147 (1): 222-229. 10.1006/cimm.1993.1062.CrossRefPubMed
11.
go back to reference Moskalev AA, Shaposhnikov MV: Pharmacological inhibition of phosphoinositide 3 and tor kinases improves survival of Drosophila melanogaster. Rejuvenation Res. 2010, 13 (2–3): 246-247. 10.1089/rej.2009.0903.CrossRefPubMed Moskalev AA, Shaposhnikov MV: Pharmacological inhibition of phosphoinositide 3 and tor kinases improves survival of Drosophila melanogaster. Rejuvenation Res. 2010, 13 (2–3): 246-247. 10.1089/rej.2009.0903.CrossRefPubMed
12.
go back to reference Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C: A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 2008, 4 (2): e24-10.1371/journal.pgen.0040024.PubMedCentralCrossRefPubMed Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C: A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 2008, 4 (2): e24-10.1371/journal.pgen.0040024.PubMedCentralCrossRefPubMed
13.
go back to reference Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R: Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011, 66 (2): 191-201. 10.1093/gerona/glq178.CrossRefPubMed Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R: Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011, 66 (2): 191-201. 10.1093/gerona/glq178.CrossRefPubMed
15.
16.
go back to reference Nunes-Alves C, Booty MG, Carpenter SM, Jayaraman P, Rothchild AC, Behar SM: In search of a new paradigm for protective immunity to tb. Nat Rev Microbiol. 2014, 12 (4): 289-299. 10.1038/nrmicro3230.PubMedCentralCrossRefPubMed Nunes-Alves C, Booty MG, Carpenter SM, Jayaraman P, Rothchild AC, Behar SM: In search of a new paradigm for protective immunity to tb. Nat Rev Microbiol. 2014, 12 (4): 289-299. 10.1038/nrmicro3230.PubMedCentralCrossRefPubMed
17.
go back to reference Andersen P, Woodworth JS: Tuberculosis vaccines–rethinking the current paradigm. Trends Immunol. 2014, 35 (8): 387-395. 10.1016/j.it.2014.04.006.CrossRefPubMed Andersen P, Woodworth JS: Tuberculosis vaccines–rethinking the current paradigm. Trends Immunol. 2014, 35 (8): 387-395. 10.1016/j.it.2014.04.006.CrossRefPubMed
18.
go back to reference Modlin RL, Bloom BR: TB or not TB: That is no longer the question. Sci Transl Med. 2013, 5 (213): 213sr6-10.1126/scitranslmed.3007402.CrossRefPubMed Modlin RL, Bloom BR: TB or not TB: That is no longer the question. Sci Transl Med. 2013, 5 (213): 213sr6-10.1126/scitranslmed.3007402.CrossRefPubMed
19.
go back to reference Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009, 460 (7253): 392-395.PubMedCentralPubMed Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009, 460 (7253): 392-395.PubMedCentralPubMed
20.
go back to reference Beamer GL, Cyktor J, Flaherty DK, Stromberg PC, Carruthers B, Turner J: CBA/J mice generate protective immunity to soluble ag85 but fail to respond efficiently to ag85 during natural Mycobacterium tuberculosis infection. Eur J Immunol. 2012, 42 (4): 870-879. 10.1002/eji.201142054.PubMedCentralCrossRefPubMed Beamer GL, Cyktor J, Flaherty DK, Stromberg PC, Carruthers B, Turner J: CBA/J mice generate protective immunity to soluble ag85 but fail to respond efficiently to ag85 during natural Mycobacterium tuberculosis infection. Eur J Immunol. 2012, 42 (4): 870-879. 10.1002/eji.201142054.PubMedCentralCrossRefPubMed
21.
go back to reference Beamer GL, Flaherty DK, Vesosky B, Turner J: Peripheral blood gamma interferon release assays predict lung responses and Mycobacterium tuberculosis disease outcome in mice. Clin Vaccine Immunol. 2008, 15 (3): 474-483. 10.1128/CVI.00408-07.PubMedCentralCrossRefPubMed Beamer GL, Flaherty DK, Vesosky B, Turner J: Peripheral blood gamma interferon release assays predict lung responses and Mycobacterium tuberculosis disease outcome in mice. Clin Vaccine Immunol. 2008, 15 (3): 474-483. 10.1128/CVI.00408-07.PubMedCentralCrossRefPubMed
22.
go back to reference Logan RW, Robledo RF, Recla JM, Philip VM, Bubier JA, Jay JJ, Harwood C, Wilcox T, Gatti DM, Bult CJ, Churchill GA, Chesler EJ: High-precision genetic mapping of behavioral traits in the diversity outbred mouse population. Genes Brain Behav. 2013, 12 (4): 424-437. 10.1111/gbb.12029.PubMedCentralCrossRefPubMed Logan RW, Robledo RF, Recla JM, Philip VM, Bubier JA, Jay JJ, Harwood C, Wilcox T, Gatti DM, Bult CJ, Churchill GA, Chesler EJ: High-precision genetic mapping of behavioral traits in the diversity outbred mouse population. Genes Brain Behav. 2013, 12 (4): 424-437. 10.1111/gbb.12029.PubMedCentralCrossRefPubMed
23.
go back to reference Recla JM, Robledo RF, Gatti DM, Bult CJ, Churchill GA, Chesler EJ: Precise genetic mapping and integrative bioinformatics in diversity outbred mice reveals hydin as a novel pain gene. Mamm Genome. 2014, 25 (5-6): 211-222. 10.1007/s00335-014-9508-0.PubMedCentralCrossRefPubMed Recla JM, Robledo RF, Gatti DM, Bult CJ, Churchill GA, Chesler EJ: Precise genetic mapping and integrative bioinformatics in diversity outbred mice reveals hydin as a novel pain gene. Mamm Genome. 2014, 25 (5-6): 211-222. 10.1007/s00335-014-9508-0.PubMedCentralCrossRefPubMed
24.
go back to reference Flurkey K, Astle CM, Harrison DE: Life extension by diet restriction and n-acetyl-l-cysteine in genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2010, 65 (12): 1275-1284. 10.1093/gerona/glq155.CrossRefPubMed Flurkey K, Astle CM, Harrison DE: Life extension by diet restriction and n-acetyl-l-cysteine in genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2010, 65 (12): 1275-1284. 10.1093/gerona/glq155.CrossRefPubMed
25.
go back to reference Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, Sabatini DM, Harrison DE, Vang O, Baur JA: Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY). 2013, 5 (7): 539-550. Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, Sabatini DM, Harrison DE, Vang O, Baur JA: Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY). 2013, 5 (7): 539-550.
26.
go back to reference Beamer GL, Turner J: Murine models of susceptibility to tuberculosis. Arch Immunol Ther Exp (Warsz). 2005, 53 (6): 469-483. Beamer GL, Turner J: Murine models of susceptibility to tuberculosis. Arch Immunol Ther Exp (Warsz). 2005, 53 (6): 469-483.
27.
go back to reference Major S, Turner J, Beamer G: Tuberculosis in CBA/J mice. Vet Pathol. 2013, 50 (6): 1016-1021. 10.1177/0300985813482952.CrossRefPubMed Major S, Turner J, Beamer G: Tuberculosis in CBA/J mice. Vet Pathol. 2013, 50 (6): 1016-1021. 10.1177/0300985813482952.CrossRefPubMed
28.
go back to reference Flynn JL, Chan J: Immunology of tuberculosis. Annu Rev Immunol. 2001, 19: 93-129. 10.1146/annurev.immunol.19.1.93.CrossRefPubMed Flynn JL, Chan J: Immunology of tuberculosis. Annu Rev Immunol. 2001, 19: 93-129. 10.1146/annurev.immunol.19.1.93.CrossRefPubMed
31.
go back to reference Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Eissa NT: Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009, 15 (3): 267-276. 10.1038/nm.1928.CrossRefPubMed Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Eissa NT: Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009, 15 (3): 267-276. 10.1038/nm.1928.CrossRefPubMed
32.
go back to reference Gupta A, Pant G, Mitra K, Madan J, Chourasia MK, Misra A: Inhalable particles containing rapamycin for induction of autophagy in macrophages infected with Mycobacterium tuberculosis. Mol Pharm. 2014, 11 (4): 1201-1207. 10.1021/mp4006563.CrossRefPubMed Gupta A, Pant G, Mitra K, Madan J, Chourasia MK, Misra A: Inhalable particles containing rapamycin for induction of autophagy in macrophages infected with Mycobacterium tuberculosis. Mol Pharm. 2014, 11 (4): 1201-1207. 10.1021/mp4006563.CrossRefPubMed
33.
go back to reference Deretic V: Autophagy, an immunologic magic bullet: Mycobacterium tuberculosis phagosome maturation block and how to bypass it. Future Microbiol. 2008, 3 (5): 517-524. 10.2217/17460913.3.5.517.PubMedCentralCrossRefPubMed Deretic V: Autophagy, an immunologic magic bullet: Mycobacterium tuberculosis phagosome maturation block and how to bypass it. Future Microbiol. 2008, 3 (5): 517-524. 10.2217/17460913.3.5.517.PubMedCentralCrossRefPubMed
Metadata
Title
Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis
Authors
David E Harrison
Clinton M Astle
M Khalid Khan Niazi
Samuel Major
Gillian L Beamer
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Immunity & Ageing / Issue 1/2014
Electronic ISSN: 1742-4933
DOI
https://doi.org/10.1186/s12979-014-0024-6

Other articles of this Issue 1/2014

Immunity & Ageing 1/2014 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine