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Microbiology and Immunology Oct 2023The high mortality rate associated with Listeria monocytogenes can be attributed to its ability to invade the body systemically and to activate inflammasomes. Both of... (Review)
Review
The high mortality rate associated with Listeria monocytogenes can be attributed to its ability to invade the body systemically and to activate inflammasomes. Both of these processes are facilitated by expressing a major virulence factor known as listeriolysin O, a 56 kDa pore-forming protein encoded by the hly gene. Listeriolysin O plays a crucial role in the pathogenesis of the bacterium by facilitating the escape of the pathogen from the phagosome into the cytosol. This process is essential for the successful establishment of infection. In addition, listeriolysin O is known as an immunomodulator that activates host signal transduction. In addition to listeriolysin O, Listeria expresses a variety of bacterial ligands, such as lipoteichoic acid, nucleotide, and flagellin, that are recognized by host intracellular pattern-recognition receptors including Nod-like receptors, AIM2-like receptors, and RIG-I-like receptors. This review introduces intracellular recognition of Listeria monocytogenes since recent studies have revealed that the activation of inflammasome exacerbates Gram-positive bacteria infection.
Topics: Humans; Listeria monocytogenes; Inflammasomes; Hemolysin Proteins; Phagosomes; Cytosol; Virulence Factors; Listeriosis
PubMed: 37461376
DOI: 10.1111/1348-0421.13091 -
Frontiers in Immunology 2023Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe... (Review)
Review
Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe infections, the f fatality rate of sepsis remains high, and the threat of antimicrobial-resistant bacteria grows with time, putting us at inferiority. Although tremendous resources have been devoted to the development of antimicrobial agents, we have yet to recover from the lost ground we have been driven into. Looking back at the evolution of treatment for cancer, which, like infectious diseases, has the similarity that host immunity eliminates the lesion, the development of drugs to eliminate the tumor itself has shifted from a single-minded focus on drug development to the establishment of a treatment strategy in which the de-suppression of host immunity is another pillar of treatment. In infectious diseases, on the other hand, the development of therapies that strengthen and support the immune system has only just begun. Among innate immunity, the first line of defense that bacteria encounter after invading the host, the molecular mechanisms of the phagolysosome pathway, which begins with phagocytosis to fusion with lysosome, have been elucidated in detail. Bacteria have a large number of strategies to escape and survive the pathway. Although the full picture is still unfathomable, the molecular mechanisms have been elucidated for some of them, providing sufficient clues for intervention. In this article, we review the host defense mechanisms and bacterial evasion mechanisms and discuss the possibility of host-directed therapy for bacterial infection by intervening in the phagolysosome pathway.
Topics: Humans; Bacterial Infections; Immunity, Innate; Anti-Infective Agents; Bacteria; Phagosomes; Communicable Diseases
PubMed: 37841276
DOI: 10.3389/fimmu.2023.1227467 -
International Journal of Medical... Jan 2018Intracellular pathogens invade their host cells and replicate within specialized compartments. In turn, the host cell initiates a defensive response trying to kill the... (Review)
Review
Intracellular pathogens invade their host cells and replicate within specialized compartments. In turn, the host cell initiates a defensive response trying to kill the invasive agent. As a consequence, intracellular lifestyle implies morphological and physiological changes in both pathogen and host cell. Leishmania spp. are medically important intracellular protozoan parasites that are internalized by professional phagocytes such as macrophages, and reside within the parasitophorous vacuole inhibiting their microbicidal activity. Whereas the proteome of the extracellular promastigote form and the intracellular amastigote form have been extensively studied, the constituents of Leishmania's intracellular niche, an endolysosomal compartment, are not fully deciphered. In this review we discuss protocols to purify such compartments by means of an illustrating example to highlight generally relevant considerations and innovative aspects that allow purification of not only the intracellular parasites but also the phagosomes that harbor them and analyze the latter by gel free proteomics.
Topics: Animals; Humans; Leishmania; Leishmaniasis; Lysosomes; Macrophages; Phagosomes; Proteome; Proteomics; Protozoan Proteins
PubMed: 28927848
DOI: 10.1016/j.ijmm.2017.09.003 -
The EMBO Journal Dec 2022Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes....
Phagocytosis is a key process in innate immunity and homeostasis. After particle uptake, newly formed phagosomes mature by acquisition of endolysosomal enzymes. Macrophage activation by interferon gamma (IFN-γ) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-γ activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-γ activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.
Topics: Animals; Mice; Bacterial Infections; Interferon-gamma; Phagocytosis; Phagosomes; Staphylococcus aureus; Ubiquitin-Protein Ligases
PubMed: 36281581
DOI: 10.15252/embj.2021108970 -
Trends in Immunology Jan 2023Prophylactic vaccination strategies designed to prevent diseases caused by pathogens using the phagolysosome of innate immune cells as a site of intracellular... (Review)
Review
Prophylactic vaccination strategies designed to prevent diseases caused by pathogens using the phagolysosome of innate immune cells as a site of intracellular replication and survival have been largely ineffective. These include Mycobacterium tuberculosis (Mtb), Leishmania spp., and Cryptococcus spp. These failed strategies have traditionally targeted CD4 T helper (Th) 1 cell-mediated immune memory, deeming it crucial for vaccine efficacy. This failure warrants an investigation of alternative mediators of protection. Here, we suggest three novel approaches to activate phagocytic cells prior to or at the time of infection. We hypothesize that preventing the formation of the pathogen niche within the phagolysosome is essential for preventing disease, and a greater emphasis on the timing of phagocyte activation should generate more effective prophylactic treatment options.
Topics: Humans; Mycobacterium tuberculosis; Immunologic Memory; T-Lymphocytes, Helper-Inducer; Phagosomes
PubMed: 36494273
DOI: 10.1016/j.it.2022.11.004 -
Trends in Biochemical Sciences Nov 2016Research in the past decade has established the importance of autophagy to a large number of physiological processes and pathophysiological conditions. Originally... (Review)
Review
Research in the past decade has established the importance of autophagy to a large number of physiological processes and pathophysiological conditions. Originally characterized as a pathway responsible for protein turnover and recycling of amino acids in times of starvation, it has been recently recognized as a major regulator of lipid metabolism. Different lipid species play various roles in the regulation of autophagosomal biogenesis, both as membrane constituents and as signaling platforms. Distinct types of autophagy, in turn, facilitate specific steps in metabolic pathways of different lipid classes, best exemplified in recent studies on neutral lipid dynamics. We review the emerging notion of intricate links between phospholipids, autophagy, and neutral lipids.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Biological Transport; Cell Membrane; Eukaryotic Cells; Gene Expression Regulation; Humans; Lipid Metabolism; Membrane Proteins; Mice; Organelle Biogenesis; Phagosomes; Phosphatidic Acids; Phosphatidylethanolamines; Phosphatidylinositols; Signal Transduction
PubMed: 27595473
DOI: 10.1016/j.tibs.2016.08.001 -
International Reviews of Immunology 2020Phagocytosis is a pivotal immunological process, and its discovery by Elia Metchnikoff in 1882 was a step toward the establishment of the innate immune system as a... (Review)
Review
Phagocytosis is a pivotal immunological process, and its discovery by Elia Metchnikoff in 1882 was a step toward the establishment of the innate immune system as a separate branch of immunology. Elia Metchnikoff received the Nobel Prize in physiology and medicine for this discovery in 1908. Since its discovery almost 140 years before, phagocytosis remains the hot topic of research in immunology. The phagocytosis research has seen a great advancement since its first discovery. Functionally, phagocytosis is a simple immunological process required to engulf and remove pathogens, dead cells and tumor cells to maintain the immune homeostasis. However, mechanistically, it is a very complex process involving different mechanisms, induced and regulated by several pattern recognition receptors, soluble pattern recognition molecules, scavenger receptors (SRs) and opsonins. These mechanisms involve the formation of phagosomes, their maturation into phagolysosomes causing pathogen destruction or antigen synthesis to present them to major histocompatibility complex molecules for activating an adaptive immune response. Any defect in this mechanism may predispose the host to certain infections and inflammatory diseases (autoinflammatory and autoimmune diseases) along with immunodeficiency. The article is designed to discuss its mechanistic complexity at each level, varying from phagocytosis induction to phagolysosome resolution.
Topics: Animals; Autoimmune Diseases; Homeostasis; Humans; Immunity, Innate; Infections; Phagocytosis; Phagosomes; Receptors, Pattern Recognition; Receptors, Scavenger
PubMed: 32141349
DOI: 10.1080/08830185.2020.1732958 -
Biochimica Et Biophysica Acta.... Jul 2021Listeria monocytogenes is an intracellular food-borne pathogen that causes listeriosis, a severe and potentially life-threatening disease. Listeria uses a number of... (Review)
Review
Listeria monocytogenes is an intracellular food-borne pathogen that causes listeriosis, a severe and potentially life-threatening disease. Listeria uses a number of virulence factors to proliferate and spread to various cells and tissues. In this process, three bacterial virulence factors, the pore-forming protein listeriolysin O and phospholipases PlcA and PlcB, play a crucial role. Listeriolysin O belongs to a family of cholesterol-dependent cytolysins that are mostly expressed by gram-positive bacteria. Its unique structural features in an otherwise conserved three-dimensional fold, such as the acidic triad and proline-glutamate-serine-threonine-like sequence, enable the regulation of its intracellular activity as well as distinct extracellular functions. The stability of listeriolysin O is pH- and temperature-dependent, and this provides another layer of control of its activity in cells. Moreover, many recent studies have demonstrated a unique mechanism of pore formation by listeriolysin O, i.e., the formation of arc-shaped oligomers that can subsequently fuse to form membrane defects of various shapes and sizes. During listerial invasion of host cells, these membrane defects can disrupt phagosome membranes, allowing bacteria to escape into the cytosol and rapidly multiply. The activity of listeriolysin O is profoundly dependent on the amount and accessibility of cholesterol in the lipid membrane, which can be modulated by the phospholipase PlcB. All these prominent features of listeriolysin O play a role during different stages of the L. monocytogenes life cycle by promoting the proliferation of the pathogen while mitigating excessive damage to its replicative niche in the cytosol of the host cell.
Topics: Bacterial Proteins; Bacterial Toxins; Cholesterol; Heat-Shock Proteins; Hemolysin Proteins; Listeria monocytogenes; Membrane Lipids; Phagosomes; Protein Binding; Protein Stability; Type C Phospholipases; Virulence
PubMed: 33722646
DOI: 10.1016/j.bbamem.2021.183604 -
Neurobiology of Aging Aug 2023Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and dysfunction in the retinal pigment epithelium (RPE) with age is known to...
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and dysfunction in the retinal pigment epithelium (RPE) with age is known to contribute to disease development. The aim of this study was to investigate how the C57BL/6J mouse RPE changes with age. RPE structure was found to change with age and eccentricity, with cell size increasing, nuclei lost, and tight junctions altered in the peripheral retina. Phagocytosis of photoreceptor outer segments (POS) by the RPE was investigated using gene expression analysis and histology. RNA-Seq transcriptomic gene profiling of the RPE showed a downregulation of genes involved in phagosome processing and histological analysis showed a decline in phagosome-lysosome association in the aged tissue. In addition, failures in the autophagy pathway that modulates intracellular waste degradation were observed in the aged RPE tissue. These findings highlight that RPE cell loss and slowing of POS processing contribute to RPE dysfunction with age and may predispose the aging eye to AMD development.
Topics: Mice; Animals; Retinal Pigment Epithelium; Mice, Inbred C57BL; Phagocytosis; Phagosomes; Aging
PubMed: 37130462
DOI: 10.1016/j.neurobiolaging.2023.03.003 -
Current Biology : CB Feb 2023Phagocytic clearance is important to provide cells with metabolites and regulate immune responses, but little is known about how phagolysosomes finally resolve their...
Phagocytic clearance is important to provide cells with metabolites and regulate immune responses, but little is known about how phagolysosomes finally resolve their phagocytic cargo of cell corpses, cell debris, and pathogens. While studying the phagocytic clearance of non-apoptotic polar bodies in C. elegans, we previously discovered that phagolysosomes tubulate into small vesicles to facilitate corpse clearance within 1.5 h. Here, we show that phagolysosome vesiculation depends on amino acid export by the solute transporter SLC-36.1 and the activation of TORC1. We demonstrate that downstream of TORC1, BLOC-1-related complex (BORC) is de-repressed by Ragulator through the BORC subunit BLOS-7. In addition, the BORC subunit SAM-4 is needed continuously to recruit the small GTPase ARL-8 to the phagolysosome for tubulation. We find that disrupting the regulated GTP-GDP cycle of ARL-8 reduces tubulation by kinesin-1, delays corpse clearance, and mislocalizes ARL-8 away from lysosomes. We also demonstrate that mammalian phagocytes use BORC to promote phagolysosomal degradation, confirming the conserved importance of TOR and BORC. Finally, we show that HOPS is required after tubulation for the rapid degradation of cargo in small phagolysosomal vesicles, suggesting that additional rounds of lysosome fusion occur. Thus, by observing single phagolysosomes over time, we identified the molecular pathway regulating phagolysosome vesiculation that promotes efficient resolution of phagocytosed cargos.
Topics: Animals; Apoptosis; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Lysosomes; Mammals; Mechanistic Target of Rapamycin Complex 1; Phagocytosis; Phagosomes; Multiprotein Complexes
PubMed: 36652947
DOI: 10.1016/j.cub.2022.12.041