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Hypoxic Response of Mycobacterium tuberculosis Studied by Metabolic Labeling and Proteome Analysis of Cellular and Extracellular Proteins

Ida Rosenkrands,^1* Richard A. Slayden,^2, Janne Crawford,³ Claus Aagaard,¹ Clifton E., III Barry,² and Peter Andersen¹

Department of TB Immunology, Statens Serum Institut, Copenhagen,¹ MDS Protana, Odense, Denmark,³ Tuberculosis Research Section, National Institute of Allergy and Infectious Disease, Rockville, Maryland²

Received 10 December 2002/ Accepted 4 April 2002

The events involved in the establishment of a latent infection with Mycobacterium tuberculosis are not fully understood, but hypoxic conditions are generally believed to be the environment encountered by the pathogen in the central part of the granuloma. The present study was undertaken to provide insight into M. tuberculosis protein expression in in vitro latency models where oxygen is depleted. The response of M. tuberculosis to low-oxygen conditions was investigated in both cellular and extracellular proteins by metabolic labeling, two-dimensional electrophoresis, and protein signature peptide analysis by liquid chromatography-mass spectrometry. By peptide mass fingerprinting and immunodetection, five proteins more abundant under low-oxygen conditions were identified from several lysates of M. tuberculosis: Rv0569, Rv2031c (HspX), Rv2623, Rv2626c, and Rv3841 (BfrB). In M. tuberculosis culture filtrates, two additional proteins, Rv0363c (Fba) and Rv2780 (Ald), were found in increased amounts under oxygen limitation. These results extend our understanding of the hypoxic response in M. tuberculosis and potentially provide important insights into the physiology of the latent bacilli.

Present address: Department of Microbiology, Colorado State University, Ft. Collins, Colorado.

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