Abstract:Mycobacterium tuberculosis, the causative agent of Tuberculosis has plagued humankind for ages and has surfaced stronger than ever with the advent of drug resistance. Mycobacteria are adept at evading the host immune system and establishing infection by engaging host factors and secreting several virulence factors. Hence these secretion systems play a key role in mycobacterial pathogenesis. The type VII secretion system or ESX (early secretory antigenic target (ESAT6) secretion) system is one such crucial syst… Show more
“…The five type VII secretion systems (ESX) of M. tuberculosis secrete specific components into the host and are crucial for M. tuberculosis' virulence (61,62). Deletion of part of the ESX1 system, known as region of difference 1 (RD1), is the basis of the attenuation of the BCG vaccine (63,64).…”
Section: Virulence Factorsmentioning
confidence: 99%
“…Deletion of part of the ESX1 system, known as region of difference 1 (RD1), is the basis of the attenuation of the BCG vaccine (63,64). Apart from their role in the interactions between M. tuberculosis and its host, the ESX systems are also important for cell wall integrity and may play a role in conjugation (62,65). The RNA-seq data set revealed that the ESX systems 4 and 5 had expression levels in all stress conditions mostly similar to exponential growth (Table S2c).…”
As the goal of a bacterium is to become bacteria, evolution has imposed continued selections for gene expression. The intracellular pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, has adopted a fine-tuned response to survive its host’s methods to aggressively eradicate invaders. The development of microarrays and later RNA sequencing has led to a better understanding of biological processes controlling the relationship between host and pathogens. In this study, RNA-seq was performed to detail the transcriptomes of M. tuberculosis grown in various conditions related to stresses endured by M. tuberculosis during host infection and to delineate a general stress response incurring during persisting macrophage stresses. M. tuberculosis was subjected to long-term growth, nutrient starvation, hypoxic and acidic environments. The commonalities between these stresses point to M. tuberculosis maneuvering to exploit propionate metabolism for lipid synthesis or to withstand propionate toxicity whilst in the intracellular environment. While nearly all stresses led to a general shutdown of most biological processes, up-regulation of pathways involved in the synthesis of amino acids, cofactors, and lipids were observed only in hypoxic M. tuberculosis. This data reveals genes and gene cohorts that are specifically or exclusively induced during all of these persisting stresses. Such knowledge could be used to design novel drug targets or to define possible M. tuberculosis vulnerabilities for vaccine development. Furthermore, the disruption of specific functions from this gene set will enhance our understanding of the evolutionary forces that have caused the tubercle bacillus to be a highly successful pathogen.
“…The five type VII secretion systems (ESX) of M. tuberculosis secrete specific components into the host and are crucial for M. tuberculosis' virulence (61,62). Deletion of part of the ESX1 system, known as region of difference 1 (RD1), is the basis of the attenuation of the BCG vaccine (63,64).…”
Section: Virulence Factorsmentioning
confidence: 99%
“…Deletion of part of the ESX1 system, known as region of difference 1 (RD1), is the basis of the attenuation of the BCG vaccine (63,64). Apart from their role in the interactions between M. tuberculosis and its host, the ESX systems are also important for cell wall integrity and may play a role in conjugation (62,65). The RNA-seq data set revealed that the ESX systems 4 and 5 had expression levels in all stress conditions mostly similar to exponential growth (Table S2c).…”
As the goal of a bacterium is to become bacteria, evolution has imposed continued selections for gene expression. The intracellular pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, has adopted a fine-tuned response to survive its host’s methods to aggressively eradicate invaders. The development of microarrays and later RNA sequencing has led to a better understanding of biological processes controlling the relationship between host and pathogens. In this study, RNA-seq was performed to detail the transcriptomes of M. tuberculosis grown in various conditions related to stresses endured by M. tuberculosis during host infection and to delineate a general stress response incurring during persisting macrophage stresses. M. tuberculosis was subjected to long-term growth, nutrient starvation, hypoxic and acidic environments. The commonalities between these stresses point to M. tuberculosis maneuvering to exploit propionate metabolism for lipid synthesis or to withstand propionate toxicity whilst in the intracellular environment. While nearly all stresses led to a general shutdown of most biological processes, up-regulation of pathways involved in the synthesis of amino acids, cofactors, and lipids were observed only in hypoxic M. tuberculosis. This data reveals genes and gene cohorts that are specifically or exclusively induced during all of these persisting stresses. Such knowledge could be used to design novel drug targets or to define possible M. tuberculosis vulnerabilities for vaccine development. Furthermore, the disruption of specific functions from this gene set will enhance our understanding of the evolutionary forces that have caused the tubercle bacillus to be a highly successful pathogen.
“…As such, the SC-SVM classifier identified Mtb transcriptomes from slow-growing (i.e., dormancy-inducing), but viable conditions. In contrast, the excluded transcriptomes (total 1,940) ( Table S1 ) were from stressful conditions (e.g., drug treated, heat treated, amino acid starved) and lethal genetic perturbations (e.g., phoP , espR , mihF mutants) that reduced cell viability in Mtb cultures ( Foddai et al., 2010 ; Odermatt et al., 2018 ; Pérez et al., 2001 ; Roy et al., 2020 ; Tiwari et al., 2018 ). Figure 1 Overview schematic of DRonA/MLSynergy framework DRonA is a SC-SVM that was trained on transcriptomes from viable Mtb cultures.…”
Summary
There is an urgent need for new drug regimens to rapidly cure tuberculosis. Here, we report the development of drug response assayer (DRonA) and “MLSynergy,” algorithms to perform rapid drug response assays and predict response of
Mycobacterium tuberculosis
(Mtb) to drug combinations. Using a transcriptome signature for cell viability, DRonA detects Mtb killing by diverse mechanisms in broth culture, macrophage infection, and patient sputum, providing an efficient and more sensitive alternative to time- and resource-intensive bacteriologic assays. Further, MLSynergy builds on DRonA to predict synergistic and antagonistic multidrug combinations using transcriptomes of Mtb treated with single drugs. Together, DRonA and MLSynergy represent a generalizable framework for rapid monitoring of drug effects in host-relevant contexts and accelerate the discovery of efficacious high-order drug combinations.
“…A notable consequence of these activities is the enhanced detection by cytosolic PRRs. For example, Mycobacterium tuberculosis uses a Type VII Secretion System, termed ESX‐1, to release the membranolytic protein ESAT‐6 (also known as EsxA) into the phagosomal lumen (Roy et al., 2020). ESX‐1 and ESAT‐6 are required for a sub‐population of M .…”
Section: Bacteria‐directed Activities That Promote Pamp Access To Cytosolic Prrsmentioning
The metazoan innate immune system senses bacterial infections by detecting highly conserved bacterial molecules, termed pathogen‐associated molecular patterns (PAMPs). PAMPs are detected by a variety of host pattern recognition receptors (PRRs), whose function is to coordinate downstream immune responses. PRR activities are, in part, regulated by their subcellular localizations. Accordingly, professional phagocytes can detect extracellular bacteria and their PAMPs via plasma membrane‐oriented PRRs. Conversely, phagocytosed bacteria and their PAMPs are detected by transmembrane PRRs oriented toward the phagosomal lumen. Even though PAMPs are unable to passively diffuse across membranes, phagocytosed bacteria are also detected by PRRs localized within the host cell cytosol. This phenomenon is explained by phagocytosis of bacteria that specialize in phagosomal escape and cytosolic residence. Contrary to this cytosolic lifestyle, most bacteria studied to date spend their entire intracellular lifestyle contained within phagosomes, yet they also stimulate cytosolic PRRs. Herein, we will review our current understanding of how phagosomal PAMPs become accessible to cytosolic PRRs, as well as highlight knowledge gaps that should inspire future investigations.
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