Mycobacterial Bacilli Are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling

Authors

Adel M. Talaat, University of Wisconsin-MadisonFollow
Sarah K. Ward, University of Wisconsin—Madison
Chia-Wei Wu, University of Wisconsin—Madison
Elizabeth Rondon, University of Wisconsin—Madison
Christine Tavano, University of Wisconsin—Madison
John Bannantine, USDA ARS National Animal Disease CenterFollow
Rick Lyons, University of New Mexico Health Science Center
Stephen A. Johnston, Arizona State University, Tempe

Date of this Version

2007

Citation

JOURNAL OF BACTERIOLOGY, Vol. 189, No. 11 p. 4265–4274

doi:10.1128/JB.00011-07

Comments

U.S. government works are not subject to copyright.

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 host immunity in 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 middle stage of chronic tuberculosis, suggesting a nutrient-rich microenvironment. A total of 137 genes were significantly regulated in mid-chronic tuberculosis (45 and 60 days) compared to an 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 roles 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 regulators 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.