Unique Transcriptome Signature of Mycobacterium tuberculosis in Pulmonary Tuberculosis

Abstract

Although tuberculosis remains a substantial global threat, the mechanisms that enable mycobacterial persistence and replication within the human host are ill defined. This study represents the first genome-wide expression analysis of Mycobacterium tuberculosis from clinical lung samples, which has enabled the identification of M. tuberculosis genes actively expressed during pulmonary tuberculosis. To obtain optimal information from our DNA array analyses, we analyzed the differentially expressed genes within the context of computationally inferred protein networks. Protein networks were constructed using functional linkages established by the Rosetta stone, phylogenetic profile, conserved gene neighbor, and operon computational methods. This combined approach revealed that during pulmonary tuberculosis, M. tuberculosis actively transcribes a number of genes involved in active fortification and evasion from host defense systems. These genes may provide targets for novel intervention strategies.

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

“…Transcripts from narG, which encodes a subunit of the nitrate reductase, and narX, which lies downstream of narK2 and encodes a nonfunctional nitrate reductase, were identified in granulomas from humans with TB (25,26). This suggests that populations of mycobacteria residing within the human host are exposed to low oxygen tensions and likely respire nitrate to adapt.…”

Mycobacterium tuberculosis Transcriptome In Vivo Studies – A Key to Understand the Pathogen Adaptation Mechanism

“…Activated by INF-and non-activated mouse macrophages were used in this work as a model system. Rachman et al characterized the M. tuberculosis genes with enhanced expression in activated and inactivated mouse macrophages both relative to each other and to mycobacteria in vitro (Rachman et al, 2006). Rohde et al studied changes in the M. tuberculosis transcriptome at the initial stages of infection of mouse macrophages and demonstrated a dynamic enhancement in the expression level of some genes during the first 24 hours post infection (Rohde et al, 2007).…”

“…The report of Rachman et al published in 2006 is thus far the only work in which M. tuberculosis gene expression was studied directly in the human lungs (surgical samples) (Rachman et al, 2006). In this work, the pathogen's whole genome gene expression profiles from granuloma, pericavitary lung tissue and morphologically normal lung tissue were obtained…”

“…Among other genes of lipid metabolism expressed predominantly in vivo, there are desA genes encoding desaturases of fatty acids Li et al, 2010;Rachman et al, 2006;Schnappinger et al, 2003). The papA and pks genes, whose protein products are needed for synthesis of polyketides as components of the M. tuberculosis cell wall (Bhatt et al, 2007;Hatzios et al, 2009;Sirakova et al, 2001), are practically always transcribed in experiments.…”

“…Nevertheless, the mycobacteria are under the influence of many stress factors like active forms of oxygen and nitrogen or the apoptotic death of the host cell. The effect of stress factors induces an upregulation of genes of the DNA repair and recombination (dinF/G) systems (Rachman et al, 2006;Schnappinger et al, 2003;Talaat et al, 2004), as well as chaperon genes (groES, groEL1/2, dnaJ/K, hspX) (Fontan et al, 2008;Garton et al, 2008;Homolka et al, 2010;Karakousis et al, 2004;Rohde et al, 2007;Tailleux et al, 2008). Certain data indicate that this effect is not a specific reaction on intracellular conditions, but part of adaptive response to stress (Boshoff et al, 2004;Waddell et al, 2004).…”