Significant under expression of the DosR regulon in M. tuberculosis complex lineage 6 in sputum - 09/10/17

Doi : 10.1016/j.tube.2017.03.001

Boatema Ofori-Anyinam ^a,^b, Gregory Dolganov ^c, Tran Van ^c, J. Lucian Davis ^d,^e, Nicholas D. Walter ^f,^g,^h, Benjamin J. Garcia ^h,ⁱ, Marty Voskuil ^j, Kristina Fissette ^a, Maren Diels ^a, Michèle Driesen ^a, Conor J. Meehan ^a, Dorothy Yeboah-Manu ^k, Mireia Coscolla ^l,^m, Sebastien Gagneux ^l,^m, Martin Antonio ^b, Gary Schoolnik ^c, Florian Gehre ^a,^b,^{^{1
Both authors contributed equally to this work.}}, Bouke C. de Jong ^a,^⁎,^{^{1
Both authors contributed equally to this work.}}
^a Mycobacteriology Unit, Institute of Tropical Medicine (ITM), Nationalestraat 155, 2000, Antwerp, Belgium
^b Vaccines and Immunity Theme, Medical Research Council (MRC) Unit, The Gambia, Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, Gambia
^c Department of Microbiology and Immunology, Stanford University, 299 Campus Drive, Stanford, CA, 94305, USA
^d Department of Epidemiology of Microbial Diseases, Yale School of Public Health, 60 College Street, P.O. Box 208034, New Haven, CT, 06520-8034, USA
^e Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, P.O. Box 208057, 300 Cedar Street TAC - 441 South, New Haven, CT, 06520-8057, USA
^f Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Building 500 - 13001 E, 17th Place, Campus Box C290, Aurora, CO, 80045, USA
^g Pulmonary Section, Denver Veterans Affairs Medical Center, 1055 Clermont Street, Denver, CO, 80220, USA
^h Integrated Center for Genes, Environment, & Health, National Jewish Health, Smith Building; A647, 1400 Jackson Street, Denver, CO, 80206, USA
ⁱ Computational Bioscience Program, University of Colorado Denver, Building 500 - 13001 E, 17th Place, Campus Box C290, Aurora, CO, 80045, USA
^j Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 E. 19th Ave., Mail Stop 8333, Aurora, CO, 80045, USA
^k Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana
^l Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box 4002, Basel, Switzerland
^m University of Basel, Petersplatz 1, P.O. Box 4001, Basel, Switzerland

^∗Corresponding author.

Abstract

Mycobacterium africanum lineage (L) 6 is an important pathogen in West Africa, causing up to 40% of pulmonary tuberculosis (TB). The biology underlying the clinical differences between M. africanum and M. tuberculosis sensu stricto remains poorly understood. We performed ex vivo expression of 2179 genes of the most geographically dispersed cause of human TB, M. tuberculosis L4 and the geographically restricted, M. africanum L6 directly from sputa of 11 HIV-negative TB patients from The Gambia who had not started treatment. The DosR regulon was the most significantly decreased category in L6 relative to L4. Further, we identified nonsynonymous mutations in major DosR regulon genes of 44 L6 genomes of TB patients from The Gambia and Ghana. Using Lebek's test, we assessed differences in oxygen requirements for growth. L4 grew only at the aerobic surface while L6 grew throughout the medium. In the host, the DosR regulon is critical for M. tuberculosis in adaptation to oxygen limitation. However, M. africanum L6 appears to have adapted to growth under hypoxic conditions or to different biological niches. The observed under expression of DosR in L6 fits with the genomic changes in DosR genes, microaerobic growth and the association with extrapulmonary disease.

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Keywords : Mycobacterium africanum, Mycobacterium tuberculosis, Hypoxia, Sputum, Gene expression, DosR

Plan

Introduction

Materials and methods

Patients

Sputum collection and gene expression

Detection of Single Nucleotide Polymorphisms

Culture of M. africanum and M. tuberculosis in Lebek's medium

Results

DosR regulon gene expression in M. africanum L6

Detection of single nucleotide polymorphisms in major hypoxia response genes in M.africanum L6

M. africanum L6 preferentially grew microaerobically while M. tuberculosis L4 grew aerobically

Discussion

Conclusion

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Vol 104

P. 58-64 - mai 2017 Retour au numéro

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Significant under expression of the DosR regulon in M. tuberculosis complex lineage 6 in sputum - 09/10/17

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