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J. Bacteriol. doi:10.1128/JB.00011-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mycobacterial bacilli are metabolically active during chronic tuberculosis in murine lungs: Insights from genome-wide transcriptional profiling

The Laboratory of Bacterial Genomics, Department of Pathobiological Sciences, University of Wisconsin-Madison, WI 53706, USA; National Animal Disease Center, USDA-ARS, Ames, IA; Department of Internal Medicine, University of New Mexico Health Science Center, 915 Camino de Salud, Albuquerque, NM 87131, USA; Center for Innovations in Medicine, Arizona State University, Tempe, AZ 85287-5001, USA

^* To whom correspondence should be addressed. Email: atalaat{at}wisc.edu.

	Abstract

Chronic tuberculosis represents a major health problem for one third of the world's population today. A key question relevant to chronic tuberculosis is the physiological status of Mycobacterium tuberculosis during this important stage of infection. To examine the molecular bases of chronic tuberculosis and the role of the host immunity on mycobacterial growth, we determined the mycobacterial transcriptional profiles during chronic and reactivation phases of murine tuberculosis using in vivo microarray analysis (IVMA). Following 28 days of aerosol infection, mycobacterial counts remained stable, although the bacilli were metabolically active with a 50% active transcriptome. The expression of genes involved in lipid and carbohydrate pathways was significantly enriched during the mid stage of chronic tuberculosis suggesting a nutrient-rich microenvironment. A total of 137 genes were significantly regulated at mid-chronic tuberculosis (45 and 60 days) compared to early stage (14 days) of infection. Additional sets of genes, including the virulence regulator virS, were up-regulated during the reactivation stage indicating their possible role in mycobacterial resurgence. Interestingly, a set of potential transcriptional regulators was significantly induced at the late stage of chronic tuberculosis. Bioinformatic analysis identified a large number of genes that could be regulated by one of the potential transcriptional regulator, encoded by rv0348, including the sigF operon. Taken together, IVMA provided a better definition of the transcriptional machinery activated during chronic and reactivation stages of tuberculosis and identified a novel transcriptional regulator. A similar approach can be adopted to study key stages of intracellular pathogens.

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