TY - JOUR
T1 - Accelerated detection of Mycobacterium tuberculosis genes essential for bacterial survival in guinea pigs, compared with mice
AU - Jain, Sanjay K.
AU - Hernandez-Abanto, S. Moises
AU - Cheng, Qi Jian
AU - Singh, Prabhpreet
AU - Ly, Lan H.
AU - Klinkenberg, Lee
AU - Morrison, Norman
AU - Converse, Paul
AU - Nuermberger, Eric
AU - Grosset, Jacques
AU - McMurray, David N.
AU - Karakousis, Petros C.
AU - Lamichhane, Gyanu
AU - Bishai, William R.
N1 - Funding Information:
Received 2 November 2006; accepted 21 December 2006; electronically published 23 April 2007. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (grants and contracts AI36973, AI43846, AI37856, and N01 AI30036). a S.K.J. and S.M.H.-A. contributed equally to the study. Reprints or correspondence: Dr. Sanjay K. Jain, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans St., Baltimore, MD 21231 (sjain5@jhmi.edu).
PY - 2007/6/1
Y1 - 2007/6/1
N2 - Background. Mouse and guinea pig models have been used to identify Mycobacterium tuberculosis mutants attenuated for survival. However, unlike mice, M. tuberculosis-infected guinea pigs form caseating granulomas, which may simulate human disease more closely. Methods. We used designer arrays for defined mutant analysis, a high-throughput subtractive competition assay, for genotypically defined M. tuberculosis mutants and compared the survival of the same mutant pools in guinea pig and mouse aerosol models. Selected mutants found to be attenuated in either aerosol model were also analyzed in the mouse hollow-fiber model. Results. M. tuberculosis mutants representing 74 genes were tested. Eighteen M. tuberculosis mutants were attenuated for survival in either aerosol model, with 70% of selected mutants also attenuated in the mouse hollow-fiber model. The majority of attenuated mutants in the mouse aerosol model were detected only after 90 days of infection. There was a high degree of concordance between the genes identified by the 2 aerosol models, with detection being significantly earlier in the guinea pig (P < .0003). Conclusions. We identified M. tuberculosis genes required for survival in mammalian lungs. The majority of mouse late-stage survival mutants were detected significantly earlier in the guinea pig, which suggests that differences in tuberculosis-induced lung pathologic changes may account for this accelerated detection.
AB - Background. Mouse and guinea pig models have been used to identify Mycobacterium tuberculosis mutants attenuated for survival. However, unlike mice, M. tuberculosis-infected guinea pigs form caseating granulomas, which may simulate human disease more closely. Methods. We used designer arrays for defined mutant analysis, a high-throughput subtractive competition assay, for genotypically defined M. tuberculosis mutants and compared the survival of the same mutant pools in guinea pig and mouse aerosol models. Selected mutants found to be attenuated in either aerosol model were also analyzed in the mouse hollow-fiber model. Results. M. tuberculosis mutants representing 74 genes were tested. Eighteen M. tuberculosis mutants were attenuated for survival in either aerosol model, with 70% of selected mutants also attenuated in the mouse hollow-fiber model. The majority of attenuated mutants in the mouse aerosol model were detected only after 90 days of infection. There was a high degree of concordance between the genes identified by the 2 aerosol models, with detection being significantly earlier in the guinea pig (P < .0003). Conclusions. We identified M. tuberculosis genes required for survival in mammalian lungs. The majority of mouse late-stage survival mutants were detected significantly earlier in the guinea pig, which suggests that differences in tuberculosis-induced lung pathologic changes may account for this accelerated detection.
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U2 - 10.1086/517526
DO - 10.1086/517526
M3 - Article
C2 - 17471433
AN - SCOPUS:34249062341
SN - 0022-1899
VL - 195
SP - 1634
EP - 1642
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 11
ER -