Submitted to: Journal of Bacteriology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/13/2007
Publication Date: 6/1/2007
Citation: Talaat, A.M., Ward, S.K., Wu, C., Rondon, E., Tavano, C., Bannantine, J.P., Lyons, R., Johnston, S.A. 2007. Mycobacterial Bacilli are Metabolically Active during Chronic Tuberculosis in Murine Lungs: Insights from Genome-Wide Transcriptional Profiling. Journal of Bacteriology. 189(11):4265-4274. Interpretive Summary: This study examines the gene expression patterns that occur in Mycobacterium tuberculosis (TB) during the chronic stages of infection. A hallmark of TB pathogenesis is this latent or chronic stage where little to no clinical signs are observed. During this time, the organism can persist within the host for several years until some unknown signal reactivates the infection. By using DNA microarrays we were able to identify a list of genes actively turned on during the chronic stage infection in mice. One of these genes (Rv0348) was found to potentially regulate 136 genes involved in various aspects of chronic TB. This transcriptional regulator (Rv0348) was expressed and shown to bind DNA regions that promote gene expression in several of these 136 genes. These finding have provided several clues and new research leads into the pathogenesis and biology of persistent TB infections.
Technical 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. Previous work on chronic tuberculosis revealed that mycobacterial bacilli persist at a constant level with a very slow growth rate but did not identify the molecular basis of persistence. Characterizing key metabolic pathways activated during chronic infection will improve our understanding of the pathogenesis of M. tuberculosis. We devised an approach based on whole-genome microarrays to investigate the expression profile of M. tuberculosis during entry to the chronic stage of tuberculosis in murine lungs. Our analysis indicated that though the colonization levels of M. tuberculosis remained stable, the bacilli were metabolically active with detectable transcriptional levels in almost 50% of the genes. Interestingly, a set of potential transcriptional regulators was activated at later times during infection implying a role in mycobacterial persistence. One of these regulators (rv0348) was found to potentially regulate 136 genes involved in various aspects of chronic tuberculosis. Additional sets of genes were up-regulated during the reactivation stage indicating a possible role for mycobacterial resurgence when the host immunity is suppressed. Meta-analysis of gene expression profiles of M. tuberculosis indicated that the profile of those surviving in mouse lungs was significantly different from those surviving under hypoxic and oxidative stressors examined in vitro but was similar to those surviving in macrophage and in human lungs. Taken together, our data provide a better definition of the transcriptional machinery activated during chronic tuberculosis with unprecedented access to the mycobacterial microenvironment during infection.