The macrophages mount an effective host defense by recognizing, engulfing and killing M. tuberculosis. The recruitment of macrophages is through Toll-like receptor (TLR) mediated signaling that is triggered by pathogen activated molecular patterns (PAMPs) present on bacterial surface. The infected macrophages transport the bacteria across the lung epithelium to other tissues. Subsequently, new macrophage recruitment takes place and the original infected macrophages form granuloma, an aggregation of differentiated macrophages and other immune cells. In these granulomas the infection expands by spreading bacteria to newly arrived macrophages.
The experimental evidences suggest a link between the association of Toll-like receptor signaling, reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). Such signaling cascades lead to the activation of macrophages as an innate immune response to kill M. tuberculosis. Studies suggest that both ROI and RNI can permeabilize the cell wall/membrane of the pathogen. Most common damages that occur in DNA are the base modifications, generation of a basic sites and strand breaks in response to RNI and ROI. Specifically, ROS produces single pyrimidine and purine base lesions, intrastrand cross-links, purine 5′,8-cyclonucleosides, DNA–protein adducts and interstrand cross-links. Therefore, inability to rectify these damages in the DNA inside the macrophages can compromise its survival and ability to cause pathogenesis. Several studies suggest that M. tuberculosis is well equipped to counteract the harmful effects of ROS, RNI and low pH (<3.5) generated by the host immune system. But how the genome integrity of M. tuberculosis is maintained under these conditions continues to be an important area of research. To this end, genome-based studies in M. tuberculosis showed the involvement of various DNA repair and nucleoid associated proteins (NAPs) associated with DNA repair.
M. tuberculosis harbors all the vital genes of NER, base excision repair (BER), HR, NHEJ, SOS repair and mutagenesis, as deduced from bioinformatics and genome-based studies, but the function of these proteins and enzymes is not fully understood. Moreover, studies on DNA repair components is important considering that M. tuberculosis lacks functional mismatch repair pathway (MMR). In contrast to Helicobacter pylori, in which a correlation exists between the absence of MMR and high level of genetic diversity, M. tuberculosis genomes are very stable. This observation suggests that other DNA repair mechanisms could be very efficient in this pathogen. Recently, NucS-dependent DNA repair system that mimics the MutS/MutL based MMR has been identified in Mycobacterium smegmatis. Thus, characterization of M. tuberculosis DNA repair pathways in vivo and in vitro may contribute to the understanding of the generation of clonal populations of M. tuberculosis.
The adaptive ability of M. tuberculosis is significant in the clinical context because of its ability to supress central metabolism, halt DNA replication and enter into a stage of dormancy rendering itself extremely resistant to host defence and drug treatments. Thus, the physiological changes that take place during the shift from dormancy to reactivation of the tubercle bacillus should be investigated in detail. To this end, Affymetrix GeneChip System Microarray (based on a specific oligonucleotide array format) revealed that almost half of the DNA repair genes are continuously expressed during log phase of growth, indicating that the bacteria continuously counteract the constant exposure to DNA damaging conditions. Additionally, transposon site hybridization (TraSH) technique identified the genes, Rv2554c, dut, ligA, polA, adnB and those encoding the NER-related proteins UvrD1, UvrD2 and UvrC, are essential for optimal growth by M. tuberculosis. The uvrD2 and ligA genes were also essential for the survival of M. smegmatis.
In another study, every nonessential gene of M. tuberculosis was disrupted and their effect on the growth rate and virulence was determined in mice models. This study also revealed a set of DNA repair proteins required for survival in mice, apart from a variety of proteins from different pathways. These include three BER proteins (Ung, Nfo/End and XthA), MazG and RecN. The proteome profiling of M. tuberculosis also indicated the role of DNA repair genes during dormancy and reactivation.
Altogether, these studies suggest that most of the M. tuberculosis DNA repair genes are non-essential for survival in the broth, but disruption of these genes lead to attenuation of virulence in mice. A possible link between survival and spatial-temporal regulation of DNA repair proteins has been established by the isolation of M. tuberculosis W-Beijing strains. These strains belong to a drug resistance family which could be divided into several branches based on unique alterations in three putative antimutator genes: mutT4, mutT2 and ogt.
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