Abstract
Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population. Despite the advances in medicine and the development of effective antitubercular drugs, the cure of tuberculosis involves prolonged therapies which complicate the compliance and monitoring of drug administration and treatment. Moreover, the only available antitubercular vaccine fails to provide an effective shield against adult lung tuberculosis, which is the most prevalent form. Hence, there is a pressing need for effective antitubercular drugs and vaccines. This review highlights recent advances in the study of selected M. tuberculosis key molecular determinants of infection and vulnerable targets whose structures could be exploited for the development of new antitubercular agents.
Highlights
Mycobacterium tuberculosis is the causative agent of tuberculosis, an ancient disease which, still today, represents a major threat for the world population
Further study of the NLR family revealed that some members are capable of forming the inflammasome, a multiprotein complex composed by nucleotide oligomerisation domain (NOD) proteins which, once activated upon recognition of pathogen-associated molecules in the extracellular or the intracellular compartment, drives the activation of caspase-1 [48,49], which in turn proteolytically activates pro-IL-1β into IL-1β, the cytokine responsible for the fusion of phagosomes with lysosomes in macrophages and for triggering the early inflammatory response [18], promoting bacterial clearance
Recent research articles have provided an in-depth biochemical and structural characterisation of the UvrA and UvrB proteins that act in the first step of the Nucleotide Excision Repair (NER) pathway [119,120,121], demonstrating that UvrA proteins interact with UvrB in the absence of ligands, and suggesting this protein–protein interaction as a potential drug target for blocking the entire NER cascade in Mycobacterium tuberculosis (MTB)
Summary
The intracellular pathogen Mycobacterium tuberculosis (MTB) is the main cause of human tuberculosis (TB), the ninth cause of death worldwide, and is the leading cause of death from a single infectious agent [1]. DCs internalise the infective bacteria and present their antigens to T cells, causing their activation and initiating the onset of the adaptive immune response [13,14,15]; macrophages clear the attacking pathogens by internalising and exposing them to the acidic, hydrolytically active environment of the phagosome, eventually triggering a signalling cascade that culminates in the fusion of the lysosome to the phagosome [16]. IL-10 deactivates macrophage function by downregulating TNFα expression [27], which in turn reduces the production of IFNγ by T-cells and aids in Mtb survival All these cytokines are secreted and regulated by macrophages and DCs upon detection of specific pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) which sense.
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