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Lysosomes are an integral part of the intracellular defense system against microbes. Lysosomal homeostasis in the host is adaptable and responds to conditions such as infection or nutritional deprivation. Pathogens such as Mycobacterium tuberculosis (Mtb) and Salmonella avoid lysosomal targeting by actively manipulating the host vesicular trafficki...
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... reports suggest that different pathogens impose distinct alterations in the host lysosomal system beyond the confines of the pathogen containing vacuoles by influencing the signaling cascades regulating lysosomal homeostasis (Figure 4). Some of the factors from individual pathogens modulating lysosomal processes is summarized in Table 1, while much work remains to be done in this exciting and emerging area. ...Citations
... As the etiological agent of TB, this pathogen has developed multiple counter-strategies for surviving and persisting inside host cells. [3] It employs a range of metabolic pathways during the infection latency phase to disrupt the host's immune system and live-in organized structures that have been recognized by the host cell in response to persistent infection. [4] Moreover, when the immune system fails to kill or contain M. tuberculosis, this pathogenic agent may spread to other parts of the body. ...
... It resides within a phagosome that remains arrested at the early endosomal stage of maturation, avoiding fusion with mature lysosomes. The pH of the Mtb-containing vacuole is slightly acidic (pH 6.4), and it maintains its fusigenic nature, allowing interaction with the recycling endosomal system [61]. This is evident by the visualization of endosomal cargo, such as transferrin, passing through the Mtb-containing vacuole. ...
We examined literature on Mycobacterium tuberculosis (Mtb) subsequent to its genome release, spanning years 1999 to 2020. We employed scientometric mapping, entity mining, visualization techniques, and PubMed and PubTator databases. Most popular keywords, most active research groups, and growth in quantity of publications were determined. By gathering annotations from the PubTator, we determined direction of research in the areas of drug hypersensitivity, drug resistance(AMR), and drug-related side effects. Additionally, we examined the patterns in research on Mtb metabolism and various forms of tuberculosis, including skin, brain, pulmonary, extrapulmonary, and latent tuberculosis. We discovered that 2011 had the highest annual growth rate of publications, at 19.94%. The USA leads the world in publications with 18038, followed by China at 14441, and India at 12158. Studies on isoniazid and rifampicin resistance showed enormous increase. Non-tuberculous mycobacteria also been the subject of more research in effort to better understand Mtb physiology and as model organism. Researchers looked at co-infections like leprosy, hepatitis, plasmodium, HIV, and other opportunistic infections. Host perspectives like immune response, hypoxia, and reactive oxygen species, as well as comorbidities like arthritis, cancer, diabetes, and kidney disease etc. were also looked at. Symptomatic aspects like fever, coughing, and weight loss were also Page 2 of 56 investigated. Vitamin D has gained popularity as a supplement during illness recovery, however the interest of researchers declined off late. We delineated dominant researchers, journals, institutions, and leading nations globally, which is crucial for aligning ongoing and evolving landscape of TB research efforts. Recognising the dominant patterns offers important information about the areas of focus for current research, allowing biomedical scientists, clinicians, and organizations to strategically coordinate their efforts with the changing field of tuberculosis research.
... The role of lysosomes in killing bacterial pathogens, including Mtb is well-known [2]. ...
Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis (Mtb) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb-phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion (p62KD) blocks mitophagy flux without impacting mitochondrial quality. In p62KD cells, Mtb growth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20+ mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62KD cells, TOM20+-MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62KD cells, TOM20+-MDVs get extensively targeted to Mtb-phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb. Triggering MQC collapse in p62KD cells further diminishes Mtb survival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.
... Being lysosomes as janitor to the cell, maintenance of the lysosome's own integrity is of utmost importance for cellular homeostasis. Since cells continuously encounter different kinds of insults, which may be biotic (pathogens: Mycobacterium tuberculosis (Mtb) and Salmonella) [7] or abiotic (starvation, lysosomotropic compounds, oxidative stress [8], etc). this may disrupt lysosome homeostasis and affect the healthy functional lysosome pool. ...
In the era of personalized therapy, precise targeting of subcellular organelles holds great promise for cancer modality. Taking into consideration that lysosome represents the intersection site in numerous endosomal trafficking pathways and their modulation in cancer growth, progression, and resistance against cancer therapies, the lysosome is proposed as an attractive therapeutic target for cancer treatment. Based on the recent advances, the current review provides a comprehensive understanding of molecular mechanisms of lysosome homeostasis under 3R responses: Repair, Removal (lysophagy) and Regeneration of lysosomes. These arms of 3R responses have distinct role in lysosome homeostasis although their interdependency along with switching between the pathways still remain elusive. Recent advances underpinning the crucial role of (1) ESCRT complex dependent/independent repair of lysosome, (2) various Galectins-based sensing and ubiquitination in lysophagy and (3) TFEB/TFE proteins in lysosome regeneration/biogenesis of lysosome are outlined. Later, we also explore how these recent advancements may aid in development of phytochemicals and pharmacological agents for targeting lysosomes for efficient cancer therapy. Some of these lysosome targeting agents, which are now at various stages of clinical trials and patents, are also emphasised in this review.
... Other intracellular bacteria including Salmonella spp., Coxiella burnetii, and Mycobacterium tuberculosis have developed mechanisms to avoid lysosomal dependent clearance and reside in PCVs that promote bacterial persistence and proliferation [140,141]. Salmonella can form a PCV in nonphagocytic cells, and a role for host ESCRTs in the biogenesis of its PVC has been recently proposed [91,92]. ESCRT-III components localized to Salmonella PCVs, and bacteria invading CHMP3 knockout cells were exposed to the cytosol due to the formation of aberrant PCVs [91]. ...
The Endosomal Sorting Complex Required for Transport (ESCRT) machinery consists of multiple protein complexes that coordinate vesicle budding away from the host cytosol. ESCRTs function in many fundamental cellular processes including the biogenesis of multivesicular bodies and exosomes, membrane repair and restoration, and cell abscission during cytokinesis. Work over the past 2 decades has shown that a diverse cohort of viruses critically rely upon host ESCRT machinery for virus replication and envelopment. More recent studies reported that intracellular bacteria and the intracellular parasite Toxoplasma gondii benefit from, antagonize, or exploit host ESCRT machinery to preserve their intracellular niche, gain resources, or egress from infected cells. Here, we review how intracellular pathogens interact with the ESCRT machinery of their hosts, highlighting the variety of strategies they use to bind ESCRT complexes using short linear amino acid motifs like those used by ESCRTs to sequentially assemble on target membranes. Future work exposing new mechanisms of this molecular mimicry will yield novel insight of how pathogens exploit host ESCRT machinery and how ESCRTs facilitate key cellular processes.
... The lysosomal and pathogenic pathways indicate the dominance of these pathways used by the pathogens to avoid lysosomal targeting. They function by actively manipulating the host vesicular trafficking and reside in a vacuoles altered from the default lysosomal trafficking (Sachdeva and Sundaramurthy, 2020). The overlap of infectious disease pathways signals the usage of similar players for evading the infection and using host counterparts to reproduce. ...
Multi-drug resistant tuberculosis still remains a major public health crisis globally. With the emergence of newer active tuberculosis disease, the requirement of prolonged treatment time and adherence to therapy till its completion necessitates the search of newer therapeutics, targeting human host factors. The current work utilized statistical meta-analysis of human gene transcriptomes of active pulmonary tuberculosis disease obtained from six public datasets. The meta-analysis resulted in the identification of 2038 significantly differentially expressed genes (DEGs) in the active tuberculosis disease. The gene ontology (GO) analysis revealed that these genes were major contributors in immune responses. The pathway enrichment analyses identified from various human canonical pathways are related to other infectious diseases. In addition, the comparison of the DEGs with the tuberculosis genome wide association study (GWAS) datasets revealed the presence of few genetic variants in their proximity. The analysis of protein interaction networks (human and Mycobacterium tuberculosis) and host directed drug-target interaction network led to new candidate drug targets for drug repurposing studies. The current work sheds light on host genes and pathways enriched in active tuberculosis disease and suggest potential drug repurposing targets for host-directed therapies.
... This Lactobacillus spp.-mediated reduction in the intracellular UPEC load could be attributed to either an increased Rab27b + vesicle-dependent bacterial expulsion (14) or increased intracellular killing within BEC lysosomes (18). To distinguish between these two possibilities, we examined the intracellular bacterial burden at 6 h postexposure of UPEC-infected BECs to L. crispatus, which is the time of the likely maximal Rab27b + vesicledependent bacterial expulsion (18). ...
... This Lactobacillus spp.-mediated reduction in the intracellular UPEC load could be attributed to either an increased Rab27b + vesicle-dependent bacterial expulsion (14) or increased intracellular killing within BEC lysosomes (18). To distinguish between these two possibilities, we examined the intracellular bacterial burden at 6 h postexposure of UPEC-infected BECs to L. crispatus, which is the time of the likely maximal Rab27b + vesicledependent bacterial expulsion (18). Because we did not notice any reduction in bacterial numbers (SI Appendix, Fig. S1A) at this time point, we considered it unlikely that the enhanced expulsion of UPEC was responsible for the Lactobacillusinduced reduction in the UPEC burden. ...
Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D–mediated UPEC killing was diminished in germ-free mice and type I IFN receptor–deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.
... Besides, lysosomes can promote autophagy and the endo-lysosomal process fundamental in extracellular release pathways, playing a principal role in degrading and recycling cellular. Many studies have recently focused on the autophagy process, which represents an essential process with necrosis, apoptosis, and exocytosis [5]. Furthermore, these processes are crucial to keeping cell homeostasis, especially during stress stimulation. ...
... The images obtained from confocal microscopy were intended to investigate the cellular uptake of LLT at different times, such as 30 min, 3, and 24 hours (Figs. [3][4][5] for live cells, respectively, and 24 hours for fixed cells (Fig. 6). Some fluorescence spots in the vermilion region were obtained for LLT, and phalloidin staining was performed to delineate actin filaments and DAPI to visualize the cell nucleus. ...
Lysosomes are organelles with many functions in cell metabolism, the morphology changes as a function of the different cellular mechanisms. Some enzymes in the lysosomal medium are responsible for the cellular digestion process. This work reports a new biocompatible lysosome, the tracker, with the long-life fluorescence emission. They were investigated by steady-state, time-resolved spectroscopic, and confocal microscopy analysis in organic and biological mediums. It was observed that the probe could already be used at low concentrations to monitor lysosomes in live and fixed cell culture with selective fluorescence detection with high photostable spectroscopic. Therefore, a responsive emission in the red region of the light spectrum and the high fluorescence signal were observed even after 24 hours. The incubation time with highly selective lysosomal tracking and good response for long-time in vitro experiments, high solubility in a biological media, and reproducible signal response, with lower signal noise rates.
... Lysosomal proteases (e.g., legumain/asparagine endopeptidase) are involved in the activation of toll-like receptors (TLRs) (i.e., TLR7 and TLR9) that recognize microbial products, playing a critical role in innate and adaptive immunity [6][7][8]. Furthermore, pathogens that end up in the endo/lysosomal system (intracellular pathogens) can be killed by the hydrolytic enzymes located in lysosomes, providing the latter with defence functions during infection [9]. Moreover, lysosomerelated cytotoxic granules are critical for the elimination of virus-infected host cells and cancer cells [10,11]. ...
More than fifty years have passed since Nobel laureate Cristian de Duve described for the first time the presence of tiny subcellular compartments filled with hydrolytic enzymes: the lysosome. For a long time, lysosomes were deemed simple waste bags exerting a plethora of hydrolytic activities involved in the recycling of biopolymers, and lysosomal genes were considered to just be simple housekeeping genes, transcribed in a constitutive fashion. However, lysosomes are emerging as multifunctional signalling hubs involved in multiple aspects of cell biology, both under homeostatic and pathological conditions. Lysosomes are involved in the regulation of cell metabolism through the mTOR/TFEB axis. They are also key players in the regulation and onset of the immune response. Furthermore, it is becoming clear that lysosomal hydrolases can regulate several biological processes outside of the lysosome. They are also implicated in a complex communication network among subcellular compartments that involves intimate organelle‐to‐organelle contacts. Furthermore, lysosomal dysfunction is nowadays accepted as the causative event behind several human pathologies: low frequency inherited diseases, cancer, or neurodegenerative, metabolic, inflammatory, and autoimmune diseases. Recent advances in our knowledge of the complex biology of lysosomes have established them as promising therapeutic targets for the treatment of different pathologies. Although recent discoveries have started to highlight that lysosomes are controlled by a complex web of regulatory networks, that in some cases seem to be cell‐ and stimuli‐dependent, to harness the full potential of lysosomes as therapeutic targets we need a deeper understanding of the little‐known signalling pathways regulating this subcellular compartment and its functions.
... Depending on the phagocytosed bacterial pathogen, the default maturation of the phagosome along the endosomal-lysosomal pathway is overridden by specific pathogenic factors that interfere with the fate of the pathogen-containing vacuole (Do et al., 2016). The interference and divergence of the pathogen-containing vacuole from the default endosomal-lysosomal pathway is at the crux of the successful evolution of many intra-vacuolar pathogens to adapt to the intra-vacuolar microenvironment and inflict pathology and disease (Çakır et al., 2020;Leseigneur et al., 2020;Sachdeva and Sundaramurthy, 2020). Despite being an accidental human pathogen Legionella has evolved similar lysosomal evasion mechanisms to avoid killing by its natural amoeba hosts and human macrophages. ...
While most bacterial species taken up by macrophages are degraded through processing of the bacteria-containing vacuole through the endosomal-lysosomal degradation pathway, intravacuolar pathogens have evolved to evade degradation through the endosomal-lysosomal pathway. All intra-vacuolar pathogens possess specialized secretion systems (T3SS-T7SS) that inject effector proteins into the host cell cytosol to modulate myriad of host cell processes and remodel their vacuoles into proliferative niches. Although intravacuolar pathogens utilize similar secretion systems to interfere with their vacuole biogenesis, each pathogen has evolved a unique toolbox of protein effectors injected into the host cell to interact with, and modulate, distinct host cell targets. Thus, intravacuolar pathogens have evolved clear idiosyncrasies in their interference with their vacuole biogenesis to generate a unique intravacuolar niche suitable for their own proliferation. While there has been a quantum leap in our knowledge of modulation of phagosome biogenesis by intravacuolar pathogens, the detailed biochemical and cellular processes affected remain to be deciphered. Here we discuss how the intravacuolar bacterial pathogens Salmonella, Chlamydia, Mycobacteria, Legionella, Brucella, Coxiella, and Anaplasma utilize their unique set of effectors injected into the host cell to interfere with endocytic, exocytic, and ER-to-Golgi vesicle traffic. However, Coxiella is the main exception for a bacterial pathogen that proliferates within the hydrolytic lysosomal compartment, but its T4SS is essential for adaptation and proliferation within the lysosomal-like vacuole.
