Abstract:Mycobacterium tuberculosis (Mtb) modulates diverse cell death pathways to escape the host immune responses and favor its dissemination, a complex process of interest in pathogenesis-related studies. The main virulence factors of Mtb that alter cell death pathways are classified according to their origin as either non-protein (for instance, lipomannan) or protein (such as the PE family and ESX secretion system). The 38 kDa lipoprotein, ESAT-6 (early antigen-secreted protein 6 kDa), and another secreted protein,… Show more
“…Here, we showed that early infection with virulent Mtb begins with small foci of infection stemming from the upper airways, which eventually disseminates to the lower areas of the lung. This is in line with studies that have shown that Mtb virulence proteins drives tissue destruction early on and allows infected macrophages to depart the primary granuloma and disseminate the infection 27 .…”
Tuberculosis (TB) is characterized by the formation of heterogenous, immune-rich granulomas present in various forms in the lungs. Both host and pathogen contribute to this heterogeneity however the molecular and cellular drivers of within-host granuloma heterogeneity remain to be fully elucidated. This knowledge gap is due to a lack of experimental approaches that can fully capture the complex dynamics of the lung architecture, dynamics of host-pathogen interplay and pathogenesis. Here, we developed an approach that combines PACT-based clearing with light sheet fluorescent microscopy for visualizing lesion architecture development and lung involvement inM. tuberculosis-infected C3HeB/FeJ susceptible mice. This 3D modelling of whole lung lobes approach revealed critical architectural features in lesion development and lung involvement that were not apparent using traditional thin section imaging. Wild typeM. tuberculosisinfection triggered a clear and well-organized granulomatous-like organization with substantial growth throughout the infection period that invaded a high percentage of the total lung volume. In contrast, infection with the avirulent ESX-1 deletion mutant strainMtbΔRD1 showed an altered growth pattern with diffuse and sparsely organized CD11b recruitment to sites of infection. Moreover, most of theMtbΔRD1-triggered lesions were present in the periphery of the lungs and did not display any formal organization. We further provide a novel way of interrogating PACT-cleared tissue for high ultrastructural content using volumetric correlative light and electron microscopy, allowing individual immune cell populations to be tracked and their fate within the granuloma captured. Ultimately, the combination of both modalities allowed an unprecedented view of the architectural distribution ofM. tuberculosisin the lungs and the progression of lesion development over time. Our data highlight that ESX-1 fromM. tuberculosisis required for lesion architecture progression in a susceptible mouse model of TB.
“…Here, we showed that early infection with virulent Mtb begins with small foci of infection stemming from the upper airways, which eventually disseminates to the lower areas of the lung. This is in line with studies that have shown that Mtb virulence proteins drives tissue destruction early on and allows infected macrophages to depart the primary granuloma and disseminate the infection 27 .…”
Tuberculosis (TB) is characterized by the formation of heterogenous, immune-rich granulomas present in various forms in the lungs. Both host and pathogen contribute to this heterogeneity however the molecular and cellular drivers of within-host granuloma heterogeneity remain to be fully elucidated. This knowledge gap is due to a lack of experimental approaches that can fully capture the complex dynamics of the lung architecture, dynamics of host-pathogen interplay and pathogenesis. Here, we developed an approach that combines PACT-based clearing with light sheet fluorescent microscopy for visualizing lesion architecture development and lung involvement inM. tuberculosis-infected C3HeB/FeJ susceptible mice. This 3D modelling of whole lung lobes approach revealed critical architectural features in lesion development and lung involvement that were not apparent using traditional thin section imaging. Wild typeM. tuberculosisinfection triggered a clear and well-organized granulomatous-like organization with substantial growth throughout the infection period that invaded a high percentage of the total lung volume. In contrast, infection with the avirulent ESX-1 deletion mutant strainMtbΔRD1 showed an altered growth pattern with diffuse and sparsely organized CD11b recruitment to sites of infection. Moreover, most of theMtbΔRD1-triggered lesions were present in the periphery of the lungs and did not display any formal organization. We further provide a novel way of interrogating PACT-cleared tissue for high ultrastructural content using volumetric correlative light and electron microscopy, allowing individual immune cell populations to be tracked and their fate within the granuloma captured. Ultimately, the combination of both modalities allowed an unprecedented view of the architectural distribution ofM. tuberculosisin the lungs and the progression of lesion development over time. Our data highlight that ESX-1 fromM. tuberculosisis required for lesion architecture progression in a susceptible mouse model of TB.
Tuberculosis (TB) stands as the second most prevalent cause of global human mortality from infectious diseases. In 2022, the World Health Organization documented an estimated number of global TB cases reaching 7.5 million, which causes death for 1.13 million patients. The continuous growth of drug-resistant TB cases due to various mutations in the
Mycobacterium tuberculosis
(MTB) strain, raises the urgency of the exploration of novel anti-TB treatments. Ursolic acid (UA) is a natural pentacyclic triterpene found in various plants that has shown potential as a novel anti-TB agent. This review aims to provide an overview of the therapeutic prospects of UA against MTB, with a particular emphasis on in silico, in vitro, and in vivo studies. Various mechanisms of action of UA against MTB are briefly recapped from in silico studies, such as enoyl acyl carrier protein reductase inhibitors, FadA5 (Acetyl-CoA acetyltransferase) inhibitors, tuberculosinyl adenosine transferase inhibitors, and small heat shock protein 16.3 inhibitor. The potential of UA to overcome drug resistance and its synergistic effects with existing antituberculosis drugs are briefly explained from in vitro studies using a variety of methods, such as Microplate Alamar Blue Assay, Mycobacteria Growth Indicator Tube 960 and Resazurin Assays, morphological change evaluation using transmission electron microscopy, and in vivo studies using BALB/C infected with multi drug resistant clinical isolates. Besides its promising mechanism as an antituberculosis drug, its complex chemical composition, limited availability and supply, and lack of intellectual property are also reviewed as those are the most frequently occurring challenges that need to be addressed for the successful development of UA as novel anti-TB agent.
“…It is interesting to note that MTB is extremely adapted to survive under the extreme conditions that lie within the macrophages and other cells of the immune system. In addition to possessing an incredible capacity to modulate not only its metabolism and cell division under these conditions but also, manipulate the immune responses of the host [16,118,180,[217][218][219][220].…”
Section: Who Are Mtb? the Genes Answer The Questionmentioning
Mycobacterium tuberculosis is the agent of tuberculosis, one of the most important infectious diseases in the world. This microorganism stands out from other bacteria, not only for its extremely high infection capacity, but also for its cellular characteristics that include an extremely resistant and hydrophobic cellular parade the passage of antibiotics. An incredible ability to adapt to adverse conditions inside the host as well as its vast arsenal of virulence factors that allow its survival within the inhospitable environment within the macrophage can be highlighted. This review aims to discuss several aspects of MTB microbiology, genetics, and physiology. We will address in this review details of the metabolism of MTB that allows it to replicate in the active phase and remain viable during latency, as well as the characteristics of its cell wall that contribute to the blockade of the immune response and its resistance to antibiotics.
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