Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis
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SHORT REPORT
IMMUNITY & AGEING
Open Access
Genetically diverse mice are novel and valuable models of age-associated susceptibility to Mycobacterium tuberculosis David E Harrison1†, Clinton M Astle1, M Khalid Khan Niazi2, Samuel Major3 and Gillian L Beamer3*†
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. Keywords: Tuberculosis, Rapamycin, HET3, DO, Diversity outbred, Genetically diverse population, Early Secreted Antigenic Target-6 (ESAT-6)
Findings Introduction
The importance of using genetically diverse experimental animals to model human populations was demonstrated many years ago in aging research [1] to avoid confusing a single genetic individual’s unique characteristics with those of the species. Here, we use two models of genetically diverse mice to study susceptibility to M. tuberculosis infection and immune responses to an M. tuberculosis antigen, Early Secreted Antigenic Target-6 (ESAT-6), in old mice. The first population is HET3 mice, the F2 progeny from crossing CByB6F1/J F1 hybrid females (JAX stock number 100009, [BALB/cByJ females and C57BL/6J males]) with C3D2F1/J F1 hybrid males (JAX stock number 100004, [C3H/HeJ females and DBA/2J males]). * Correspondence: [email protected] † Equal contributors 3 Tufts University Cummings School of Veterinary Medicine, 200 Westboro Road, Grafton, MA 01536, USA Full list of author information is available at the end of the article
As defined by Roderick [2], the resultant “four way cross” population is reproducible, and each HET3 mouse is genetically unique but a full sibling of all other mice in the population. We used HET3 mice in studies of primary M. tuberculosis infection and aging and in a rapamycin intervention. The second population is Diversity Outbred (DO) mice (JAX stock number 009376). DO mice are derived from the eight parental inbred strains (A/J, C57BL/6J, 129S1/ SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) [3,4], and thus are more genetically diverse than HET3 mice. W
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