The macrophage cages the invader inside what's called a phagosome, where it uses special digestive enzymes to dissolve it. Poof!
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Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using enzymes called listeriolysin O and phospholipase C.
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Moreover, C. albicans undergo yeast-to-hyphal transition within the acidic macrophage phagosome. This initially causes phagosome membrane distension which eventually leads to phagosomal alkalinization by physical rupture, followed by escape.
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The macrophage produces bacteriocidal compounds (e.g., oxygen radicals) following the respiratory burst. However, like its close relative Mycobacterium tuberculosis, R. equi prevents the fusion of the phagosome with the lysosome and acidification of the phagosome. Additionally, the respiratory burst is inhibited.
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Phagocytosis of a bacterium, showing the formation of phagosome and phagolysosome In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell membrane around a microorganism, a senescent cell or an apoptotic cell. Phagosomes have membrane-bound proteins to recruit and fuse with lysosomes to form mature phagolysosomes.
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Isotuberculosinol, also called nosyberkol or edaxadiene is a diterpene molecule produced by the bacterium Mycobacterium tuberculosis, the causative agent of TB, which aids in its pathogenesis. Isotuberculosinol functions by preventing maturation of the host-cell phagosome in which the bacterium lives. Maturation of the phagosome would enable it to kill the bacterium. Mutations in genes involved in the biosynthetic pathway of nosyberkol result in normal development of the phagosome and reduction of mycobacterial infection.
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As the fungus is thermally dimorphic, these microconidia are transformed into yeast. They grow and multiply inside the phagosome. The macrophages travel in lymphatic circulation and can spread the disease to different organs. Within the phagosome, the fungus has an absolute requirement for thiamine.
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Phagosome formation is crucial for tissue homeostasis and both innate and adaptive host defense against pathogens. However, some bacteria can exploit phagocytosis as an invasion strategy. They either reproduce inside of the phagolysosome (e.g. Coxiella spp.) or escape into the cytoplasm before the phagosome fuses with the lysosome (e.g.
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Shortly after internalisation, F-actin depolymerises from the newly formed phagosome so it becomes accessible to endosomes for fusion and delivery of proteins. The maturation process is divided into early and late stages depending on characteristic protein markers, regulated by small Rab GTPases. Rab5 is present on early phagosomes, and controls the transition to late phagosomes marked by Rab7. Rab5 recruits PI-3 kinase and other tethering proteins such as Vps34 to the phagosome membrane, so endosomes can deliver proteins to the phagosome.
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A phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested. Phagosomes fuse with lysosomes in their maturation process, forming phagolysosomes.
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It is suggested that the composition of the phagosome membrane affects the rate of maturation. Mycobacterium tuberculosis has a very hydrophobic cell wall, which is hypothesised to prevent membrane recycling and recruitment of fusion factors, so the phagosome does not fuse with lysosomes and the bacterium avoids degradation. Smaller lumenal molecules are transferred by fusion faster than larger molecules, which suggests that a small aqueous channel forms between the phagosome and other vesicles during "kiss-and-run", through which only limited exchange is allowed.
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The phagocyte then stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes. Once inside this phagocyte, the bacterium is trapped in a compartment called a phagosome. Within one minute the phagosome merges with either a lysosome or a granule to form a phagolysosome.
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As the membrane of the phagosome is formed by the fusion of the plasma membrane, the basic composition of the phospholipid bilayer is the same. Endosomes and lysosomes then fuse with the phagosome to contribute to the membrane, especially when the engulfed particle is very big, such as a parasite. They also deliver various membrane proteins to the phagosome and modify the organelle structure. Phagosomes can engulf artificial low-density latex beads and then purified along a sucrose concentration gradient, allowing the structure and composition to be studied.
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Vergne, I., J. Chua, and V. Deretic. 2003. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2!/calmodulin-PI3K hVPS34 cascade.
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In detail, a phagocyte's duty is obtaining food particles and digesting it in a vacuole.Roberts, M. B. V. Biology: A Functional Approach. Nelson Thornes. . For example, following phagocytosis, the ingested particle (or phagosome) fuses with a lysosome containing hydrolytic enzymes to form a phagolysosome; the pathogens or food particles within the phagosome are then digested by the lysosome's enzymes.
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Its cell wall prevents the fusion of the phagosome with the lysosome, which contains a host of antibacterial factors. Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carry the UreC gene, which prevents acidification of the phagosome.
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The autophagosome also fuses with lysosomes to degrade its contents. When M. tuberculosis inhibit phagosome acidification, Interferon gamma can induce autophagy and rescue the maturation process.
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The inoculum is represented principally by microconidia. These are inhaled and reach the alveoli. In the alveoli, macrophages ingest these microconidia. They survive inside the phagosome.
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TB infection begins when the mycobacteria reach the alveolar air sacs of the lungs, where they invade and replicate within endosomes of alveolar macrophages. Macrophages identify the bacterium as foreign and attempt to eliminate it by phagocytosis. During this process, the bacterium is enveloped by the macrophage and stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome then combines with a lysosome to create a phagolysosome.
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Overview of phagocytosis Phagocytosis versus exocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. The engulfing of a pathogen by a phagocyte In a multicellular organism's immune system, phagocytosis is a major mechanism used to remove pathogens and cell debris. The ingested material is then digested in the phagosome.
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Certain species in the Cytolomegavirus family can cause the infected-cell to produce proteins like US2, 3, 6, and/or 11. US11 and US2 mislead MHC I to the cytoplasm; US3 inhibits the transportation of MHC I in the ER (a part of the endogenous pathway and cross-presentation); US6 blocks peptide transportation by TAP to MHC I. Mycobacterium tuberculosis inhibits phagosome-endosome fusion, thus avoiding being destroyed by the harsh environment of the phagosome.Deretic, V., & Fratti, R. A. (1999). Mycobacterium tuberculosis phagosome.
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The bacterial proteins are denatured in low pH and become more accessible to the proteases, which are unaffected by the acidic environment. The enzymes are later recycled from the phagolysosome before egestion so they are not wasted. The composition of the phospholipid membrane also changes as the phagosome matures. Fusion may take minutes to hours depending on the contents of the phagosome; FcR or mannose receptor-mediated fusion last less than 30 minutes, but phagosomes containing latex beads may take several hours to fuse with lysosomes.
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The cytosol of the host cell contains nutrients, adenosine triphosphate, amino acids, and nucleotides which are used by the bacteria for growth. For this reason, as well as to avoid phagolysosomal fusion and death, rickettsiae must escape from the phagosome. To escape from the phagosome, the bacteria secrete phospholipase D and hemolysin C. This causes disruption of the phagosomal membrane and allows the bacteria to escape. Following generation time in the cytoplasm of the host cells, the bacteria utilizes actin based motility to move through the cytosol.
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Complement-mediated internalisation has much less significant membrane protrusions, but the downstream signalling of both pathways converge to activate Rho GTPases. They control actin polymerisation which is required for the phagosome to fuse with endosomes and lysosomes.
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Ancient single-celled organisms such as amoeba use phagocytosis as a way to acquire nutrients, rather than an immune strategy. They engulf other smaller microbes and digest them within the phagosome of around one bacterium per minute, which is much faster than professional phagocytes. For the soil amoeba Dictyostelium discoideum, their main food source is the bacteria Legionella pneumophila, which causes Legionnaire's disease in humans. Phagosome maturation in amoeba is very similar to that in macrophages, so they are used as a model organism to study the process.
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In common with many bacteria, a host cell is required for the replication of Francisella tularensis with copies of the bacteria released in a single "burst" event coinciding with the cell's death. F. tularensis is a facultative intracellular bacterium that is capable of infecting most cell types, but primarily infects macrophages in the host organism. Entry into the macrophage occurs by phagocytosis and the bacterium is sequestered from the interior of the infected cell by a phagosome. F. tularensis then breaks out of this phagosome into the cytosol and rapidly proliferates.
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Upon ingestion the antibodies no longer even sub-neutralize the body due to the denaturing condition at the step for acidification of phagosome before fusion with lysosome. The virus becomes active and begins its proliferation within the cell.
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This recycling function of the RPE protects the photoreceptors against photo-oxidative damagePhotobiology of the retina Diagrammatic representation of disc shedding and phagosome retrieval into the pigment epithelial cell and allows the photoreceptor cells to have decades-long useful lives.
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The phagosome moves along microtubules of the cytoskeleton, fusing with endosomes and lysosomes sequentially in a dynamic "kiss-and-run" manner. This intracellular transport depends on the size of the phagosomes. Larger organelles (with a diameter of about 3 µm) are transported very persistently from the cell periphery towards the perinuclear region whereas smaller organelles (with a diameter of about 1 µm) are transported more bidirectionally back and forth between cell center and cell periphery. Vacuolar proton pumps (v-ATPase) are delivered to the phagosome to acidify the organelle compartment, creating a more hostile environment for pathogens and facilitating protein degradation.
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Virulent strains of Legionella kill macrophages by blocking the fusion of phagosomes with lysosomes inside the host cell; normally, the bacteria are contained inside the phagosome, which merges with a lysosome, allowing enzymes and other chemicals to break down the invading bacteria.
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J. Exp. Med. 198:653–659.Vergne, I., R. A. Fratti, P. J. Hill, J. Chua, J. Belisle, and V. Deretic. 2004. Mycobacterium tuberculosis phagosome maturation arrest: mycobacterial phosphatidylinositol analog phosphatidylinositol mannoside stimulates early endosomal fusion. Mol. Biol. Cell 15:751–760.
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"Hemolysin" entry on TheFreeDictionary.com (Retrieved on January 22, 2009) Cytolysins may be involved in immunity as well as in venoms. Hemolysin is also used by certain bacteria, such as Listeria monocytogenes, to disrupt the phagosome membrane of macrophages and escape into the cytoplasm of the cell.
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New data indicates that ActA plays a role also in vacuolar disruption. A deletion mutant of ActA was defective in permeabilizing the vacuole. An 11 amino acid stretch of the N-terminus of the acidic region (32-42) was shown to be important for disruption of the phagosome.
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In addition to cell survival and proliferation, CERK has been implicated in many other processes. CERK is believed to participate in altering the lipid raft structure via C-1-P production, contributing to phagosome formation in polymorphonuclear leukocytes. CERK has also been found to participate in the calcium-dependent degranulation of mast cells.
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Henry Charles Mwandumba is an African Professor of Medicine and Deputy Director of the Malawi-Liverpool-Wellcome research programme. He who works on the tuberculosis phagosome in the University of Malawi College of Medicine, and serves as President of the Federation of African Immunological Societies. In 2019 Mwandumba was awarded the Royal Society Africa Prize.
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Adenovirus (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection. Brucella spp. can remain latent in a macrophage via inhibition of phagosome–lysosome fusion; causes brucellosis (undulant fever). Legionella pneumophila, the causative agent of Legionnaires' disease, also establishes residence within macrophages.
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This allows R. equi to multiply within the phagosome where it is shielded from the immune system by the very cell that was supposed to kill it. After about 48 hours, the macrophage is killed by necrosis, not apoptosis. Necrosis is pro-inflammatory, attracting additional phagocytic cells to the site of infection, eventually resulting in massive tissue damage.
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Autophagy-related protein 13 also known as ATG13 is a protein that in humans is encoded by the KIAA0652 gene. ATG13 is an autophagy factor required for phagosome formation. ATG13 is a target of the TOR kinase signaling pathway that regulates autophagy through phosphorylation of ATG13 and ULK1, and the regulation of the ATG13-ULK1-RB1CC1 complex.
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When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme uses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach. Hypochlorite is extremely toxic to bacteria. Myeloperoxidase contains a heme pigment, which accounts for the green color of secretions rich in neutrophils, such as pus and infected sputum.
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This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein complex known as NADPH oxidase found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease.
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The phagosome fuses with lysosomes to form a phagolysosome, which has various bactericidal properties. The phagolysosome contains reactive oxygen and nitrogen species (ROS and RNS) and hydrolytic enzymes. The compartment is also acidic due to proton pumps (v-ATPases) that transport H+ across the membrane, used to denature the bacterial proteins. The exact properties of phagolysosomes vary depending on the type of phagocyte.
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Macrophages and neutrophils are professional phagocytes in charge of most of the pathogen degradation, but they have different bactericidal methods. Neutrophils have granules that fuse with the phagosome. The granules contain NADPH oxidase and myeloperoxidase, which produce toxic oxygen and chlorine derivatives to kill pathogens in an oxidative burst. Proteases and anti-microbial peptides are also released into the phagolysosome.
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Degranulation of these into the phagosome, accompanied by high reactive oxygen species production (oxidative burst) is highly microbicidal. Monocytes, and the macrophages that mature from them, leave blood circulation to migrate through tissues. There they are resident cells and form a resting barrier. Macrophages initiate phagocytosis by mannose receptors, scavenger receptors, Fcγ receptors and complement receptors 1, 3 and 4.
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Thus, PIMs are important glycolipids associated with M. tuberculosis, but are also likely involved with the process by which M. tuberculosis subverts the immune system.Fratti, R. A., J. M. Backer, J. Gruenberg, S. Corvera, and V. Deretic. 2001. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154:631–644.
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Both the effectiveness and safety of hydrogen peroxide therapy is scientifically questionable. Hydrogen peroxide is produced by the immune system, but in a carefully controlled manner. Cells called phagocytes engulf pathogens and then use hydrogen peroxide to destroy them. The peroxide is toxic to both the cell and the pathogen and so is kept within a special compartment, called a phagosome.
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The nascent phagosome is not inherently bactericidal. As it matures, it becomes more acidic from pH 6.5 to pH 4, and gains characteristic protein markers and hydrolytic enzymes. The different enzymes function at various optimal pH, forming a range so they each work in narrow stages of the maturation process. Enzyme activity can be fine-tuned by modifying the pH level, allowing for greater flexibility.
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Phagosome formation is tied to inflammation via common signalling molecules. PI-3 kinase and PLC are involved in both the internalisation mechanism and triggering inflammation. The two proteins, along with Rho GTPases, are important components of the innate immune response, inducing cytokine production and activating the MAP kinase signalling cascade. Pro-inflammatory cytokines including IL-1β, IL-6, TNFα, and IL-12 are all produced.
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The most common route of infection in horses is likely via inhalation of contaminated dust particles. Inhaled virulent strains of R. equi are phagocytosed by alveolar macrophages. During normal phagocytosis, bacteria are enclosed by the phagosome, which fuses with the lysosome to become a phagolysosome. The internal environment of the phagolysosome contains nucleases and proteases, which are activated by the low pH of the compartment.
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This triggers a cascade of signal transduction events resulting in the recruitment of Arp2/3 complex. CDC42, protein tyrosine kinase, phosphoinositide 3-kinase, and Src- family kinases then activate Arp2/3. This causes the alteration of local host cytoskeletal actin at the entry site as part of a zipper mechanism. Then, the bacteria is phagocytosized by the host cell and enveloped by a phagosome.
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In addition, production of the diterpene isotuberculosinol prevents maturation of the phagosome. The bacteria also evades macrophage-killing by neutralizing reactive nitrogen intermediates. More recently, it has been shown that M. tuberculosis secretes and covers itself in 1-tuberculosinyladenosine (1-TbAd), a special nucleoside that acts as an antacid, allowing it to neutralize pH and induce swelling in lysosomes. 1-TbAd is encoded by the gene Rv3378c.
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In the neutrophil oxidative burst test heparinized whole blood is incubated at 37 °C with phorbol myristate acetate (PMA), a compound known to stimulate oxidative burst activity. Each flow cytometry pattern is referenced to the patients non- stimulated cells. In addition, a control blood is included in each run. Upon stimulation, granulocytes and monocytes produce reactive oxygen metabolites (superoxide anion, hydrogen peroxide, hypochlorous acid) which destroy bacteria inside the phagosome.
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Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. Other pathogens, such as Leishmania, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate. Some bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus, for example, produces the enzymes catalase and superoxide dismutase, which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria.
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The NOX2 enzyme is bound in the phagolysosome membrane. Post bacterial phagocytosis, it is activated, producing superoxide via its redox centre, which transfers electrons from cytosolic NADPH to O2 in the phagosome. 2O2 \+ NADPH —> 2O2•– \+ NADP+ \+ H+ The superoxide can then spontaneously or enzymatically react with other molecules to give rise to other ROS. The phagocytic membrane reseals to limit exposure of the extracellular environment to the generated reactive free radicals.
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Earthworms do not have eyes (although some worms do), however, they do have specialized photosensitive cells called "light cells of Hess". These photoreceptor cells have a central intracellular cavity (phaosome) filled with microvilli. As well as the microvilli, there are several sensory cilia in the phagosome which are structurally independent of the microvilli. The photoreceptors are distributed in most parts of the epidermis but are more concentrated on the back and sides of the worm.
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Bacteria have developed several ways of killing phagocytes. These include cytolysins, which form pores in the phagocyte's cell membranes, streptolysins and leukocidins, which cause neutrophils' granules to rupture and release toxic substances, and exotoxins that reduce the supply of a phagocyte's ATP, needed for phagocytosis. After a bacterium is ingested, it may kill the phagocyte by releasing toxins that travel through the phagosome or phagolysosome membrane to target other parts of the cell.
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In cell biology, efferocytosis (from efferre, Latin for 'to take to the grave', 'to bury') is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'. During efferocytosis, the cell membrane of phagocytic cells engulfs the apoptotic cell, forming a large fluid-filled vesicle containing the dead cell. This ingested vesicle is called an efferosome (in analogy to the term phagosome).
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Phagosomes are large enough to degrade whole bacteria, or apoptotic and senescent cells, which are usually >0.5μm in diameter. This means a phagosome is several orders of magnitude bigger than an endosome, which is measured in nanometres. Phagosomes are formed when pathogens or opsonins bind to a transmembrane receptor, which are randomly distributed on the phagocyte cell surface. Upon binding, "outside-in" signalling triggers actin polymerisation and pseudopodia formation, which surrounds and fuses behind the microorganism.
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The process is tightly regulated and the inflammatory response varies depending on the particle type within the phagosome. Pathogen-infected apoptotic cells will trigger inflammation, but damaged cells that are degraded as part of the normal tissue turnover do not. The response also differs according to the opsonin-mediated phagocytosis. FcR and mannose receptor-mediated reactions produce pro-inflammatory reactive oxygen species and arachidonic acid molecules, but CR-mediated reactions do not result in those products.
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Following internalization, the bacterium must escape from the vacuole/phagosome before fusion with a lysosome can occur. Three main virulence factors that allow the bacterium to escape are listeriolysin O (LLO- encoded by hly) phospholipase A (encoded by plcA) and phospholipase B (plcB). Secretion of LLO and PlcA disrupts the vacuolar membrane and allows the bacterium to escape into the cytoplasm, where it may proliferate. Once in the cytoplasm, L. monocytogenes exploits host actin for the second time.
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The endosymbiont dinoflagellates are used for their ability to photosynthesise and provide energy, giving the host cnidarians such as corals, and anemones, plant properties. Free-living dinoflagellates are ingested into the gastrodermal cells of the host, and their symbiosome membrane is derived from the host cell. The process of symbiosome formation is often seen in the animal host to be that of phagocytosis, and it is hypothesised that the symbiosome is a phagosome that has been subject to early arrest.
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These liposomes may be digested while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be decorated with opsonins and ligands to activate endocytosis in other cell types. The use of liposomes for transformation or transfection of DNA into a host cell is known as lipofection. In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles, pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin.
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In response to infection, the human immune system generates minute quantities of hypochlorite within special white blood cells, called neutrophil granulocytes. These granulocytes engulf viruses and bacteria in an intracellular vacuole called the phagosome, where they are digested. Part of the digestion mechanism involves an enzyme- mediated respiratory burst, which produces reactive oxygen-derived compounds, including superoxide (which is produced by NADPH oxidase). Superoxide decays to oxygen and hydrogen peroxide, which is used in a myeloperoxidase-catalysed reaction to convert chloride to hypochlorite.
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Pyroptosis has been proposed to provide immune defense by exposing cytosolic bacteria infecting the pyroptotic cell to extracellular immune defenses, including other immune cells such as neutrophils. While caspase-11-mediated pyroptosis provides defense against pathogens, it has also been shown to cause damage to the host as well. The CARD domain of caspase-11 has been shown to associate with AIP-1 and cofilin to facilitate actin depolymerization. In addition, association with the actin cytoskeleton surrounding the phagosome contributes to lysosome acidification.
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Neutrophils and other phagocytes use peroxide to kill bacteria. The enzyme NADPH oxidase generates superoxide within the phagosome, which is converted via hydrogen peroxide to other oxidising substances like hypochlorous acid which kill phagocytosed pathogens. In individuals with chronic granulomatous disease (CGD) there is a defect in producing peroxide via mutations in phagocyte oxidases such as myeloperoxidase. Normal cellular metabolism will still produce a small amount of peroxide and this peroxide can be used to produce hypochlorous acid to eradicate the bacterial infection.
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These types of membranes differ in lipid and protein composition. Distinct types of membranes also create intracellular organelles: endosome; smooth and rough endoplasmic reticulum; sarcoplasmic reticulum; Golgi apparatus; lysosome; mitochondrion (inner and outer membranes); nucleus (inner and outer membranes); peroxisome; vacuole; cytoplasmic granules; cell vesicles (phagosome, autophagosome, clathrin-coated vesicles, COPI-coated and COPII- coated vesicles) and secretory vesicles (including synaptosome, acrosomes, melanosomes, and chromaffin granules). Different types of biological membranes have diverse lipid and protein compositions. The content of membranes defines their physical and biological properties.
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From the top of the image, Entamoeba gingivalis is sipping a white cell nucleus, imperceptibly through negative suction apparently. Halfway through the process, it starts enveloping its prey in the middle, to better digest it in a future phagosome. The main activity of the amoeba Entamoeba gingivalis in the infected periodontal crevices, besides moving, consists in feeding on the nucleus of white blood cells. The amoeba penetrates into the cytoplasm to reach the nucleus and literally suctions its contents via the negative pressure of the pseudopod.
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Upon release from the phagosome, the toxin has reduced activity in the more basic cytosol. Hence, LLO permits L. monocytogenes to escape from phagosomes into the cytosol without damaging the plasma membrane of the infected cell. This allows the bacteria to live intracellularly, where they are protected from extracellular immune system factors such as the complement system and antibodies. LLO also causes dephosphorylation of histone H3 and deacetylation of histone H4 during the early phases of infection, prior to entry of L. monocytogenes into the host cell.
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The various species of Nocardia are pathogenic bacteria with low virulence; therefore clinically significant disease most frequently occurs as an opportunistic infection in those with a weak immune system, such as small children, the elderly, and the immunocompromised (most typically, HIV). Nocardial virulence factors are the enzymes catalase and superoxide dismutase (which inactivate reactive oxygen species that would otherwise prove toxic to the bacteria), as well as a "cord factor" (which interferes with phagocytosis by macrophages by preventing the fusion of the phagosome with the lysosome).
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Phagocytosis involves the internalization of solids, such as bacteria, by an organism. Phagocytosis in Three Steps Macrophages, neutrophils, and dendritic cells are all cells of the innate immune system that utilize phagocytosis and are equipped with Toll-like receptors (TLR). Toll-like receptors are present on each of these cells and recognize a variety of microbial products resulting in the induction of more specific immune responses. When a phagocytic cell engulfs bacteria, a phagosome is formed around it and the entire complex is ultimately trafficked to the lysosome for degradation.
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The vacuolar pathway is initiated through the endocytosis of an extracellular antigen by a dendritic cell. Endocytosis results in the formation of a phagocytic vesicle, where an increasingly acidic environment along with the activation of enzymes such as lysosomal proteases triggers the degradation of antigen into peptides. The peptides can then be loaded onto MHC I binding grooves within the phagosome. It is unclear whether the MHC I molecule is being exported from the endoplasmic reticulum before peptide loading, or is being recycled from the cell membrane prior to peptide loading.
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Listeriolysin O is a non-enzymatic, cytolytic, thiol-activated, cholesterol-dependent, pore-forming toxin protein; hence, it is activated by reducing agents and inhibited by oxidizing agents. However, LLO differs from other thiol-activated toxins, since its cytolytic activity is maximized at a pH of 5.5. By maximizing activity at a pH of 5.5, LLO is selectively activated within the acidic phagosomes (average pH ~ 5.9) of cells that have phagocytosed L. monocytogenes. After LLO lyses the phagosome, the bacterium escapes into the cytosol, where it can grow intracellularly.
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Once inside the cell, the invading pathogen is contained inside a phagosome, which merges with a lysosome. The lysosome contains enzymes and acids that kill and digest the particle or organism. In general, phagocytes patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. The phagocytic cells of the immune system include macrophages, neutrophils, and dendritic cells. Phagocytosis of the hosts’ own cells is common as part of regular tissue development and maintenance.
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The removal of dying cells is, to a greater extent, handled by fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed. When a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which then fuses with a lysosome. Within the phagolysosome, enzymes and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion.
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For example, phagocytosis of IgG-opsonized pathogens occurs through the Fcγ receptors (FcγR), and involves phagocyte extensions around the microbe, resulting in the production of pro-inflammatory mediators. Conversely, complement receptor-mediated pathogen ingestion occurs without observable membrane extensions (particles just sink into the cell) and does not generally results in an inflammatory mediator response. Following internalization, the microbe is enclosed in a vesicular phagosome which then undergoes fusion with primary or secondary lysosomes, forming a phagolysosome. There are various mechanisms that lead to intracellular killing; there are oxidative processes, and others independent of the oxidative metabolism.
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A recombinant BCG vaccine against Mycobacterium tuberculosis is being developed that expresses Listeriolysin O and lacks Urease C. The ΔureC hly+ rBCG vaccine has significantly higher protection than the original BCG strain due to improved antigen presentation. Listeriolysin creates pores in the phagosome and allows the bacteria to escape into the cytosol, so antigens can be presented on both Class I and Class II Major Histocompatibility Complex and activate CD8 and CD4 T-cells respectively. Urease produces ammonia and creates a basic environment which inhibits listeriolysin activity, so it is knocked out to provide the optimal pH.
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Russian scientist Élie Metchnikoff was famous for his work in microbiology and the discovery of phagocytosis. “Phagocytosis is the process by which a cell – often a phagocyte or protist – engulfs a solid particle to form an internal compartment known as a phagosome.” In 1903, he established a scientific discipline devoted to the study of death. He argued that those who were dying had few or no resources for the experience of dying and that an academic study would help those facing death to have a better understanding of the phenomenon and reduce their fear of it.
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Although type I IFN is absolutely critical for resistance to viruses, there is growing literature about the negative role of type I interferon in host immunity mediated by STING. AT-rich stem-loop DNA motif in the Plasmodium falciparum and Plasmodium berghei genome and extracellular DNA from Mycobacterium tuberculosis have been shown to activate type I interferon through STING. Perforation of the phagosome membrane mediated by ESX1 secretion system allows extracellular mycobacterial DNA to access host cytosolic DNA sensors, thus inducing the production of type I interferon in macrophages. High type I interferon signature leads to the M. tuberculosis pathogenesis and prolonged infection.
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Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.
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This method of transport is largely intercellular in lieu of uptake of large particles such as bacteria via phagocytosis in which a cell engulfs a solid particle to form an internal vesicle called a phagosome. However, much of these processes have an intracellular component. Phagocytosis is of great importance to intracellular transport because once a substance is deemed harmful and engulfed in a vesicle, it can be trafficked to the appropriate location for degradation. These endocytosed molecules are sorted into early endosomes within the cell which serves to further sort these substances to the correct final destination (in the same way the Golgi does in the secretory pathway).
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When they enter the cell, where they reside, and when they leave the cell are not known. The research is not yet conclusive but it is possible to draw a general lifecycle of D. discoideum adapted for farmer clones to better understand this symbiotic process.Lifecycle of farmer D. discoideum In the picture, one can see the different stages. First, in the starvation stage, bacteria are enclosed within D. discoideum, after entry into amoebae, in a phagosome the fusion with lysosomes is blocked and these unmatured phagosomes are surrounded by host cell organelles such as mitochondria, vesicles, and a multilayer membrane derived from the rough endoplasmic reticulum (RER) of amoebae.
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Neuronal expression of the mammalian autophagy promoting protein Beclin 1 protects mice against lethal Sindbis virus encephalitis " though the general importance of xenophagy is not yet certain.John P. Greer, John Foerster, George M. Rodgers Wintrobe's Clinical Hematology Volume 2 - Page 271 2008 "The general importance of xenophagy is not yet certain. Among the key components that are transferred to the phagosome and are critical in creating an antimicrobial environment are the vacuole ATPase, NOS2, and phagocyte oxidase ..."Issues in Biological, Biochemical, and Evolutionary Sciences "We also find that the invasive efficiency of group A Streptococcus into cells is not altered by knockdown of VAMP8 or Vti1b, whereas cellular bactericidal efficiency is significantly diminished, indicating that xenophagy is functionally impaired.
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Steps of a macrophage ingesting a pathogen After recognizing an antigen, an antigen- presenting cell such as the macrophage or B lymphocyte engulfs it completely by a process called phagocytosis. The engulfed particle, along with some material surrounding it, forms the endocytic vesicle (the phagosome), which fuses with lysosomes. Within the lysosome, the antigen is broken down into smaller pieces called peptides by proteases (enzymes that degrade larger proteins). The individual peptides are then complexed with major histocompatibility complex class II (MHC class II) molecules located in the lysosome – this method of "handling" the antigen is known as the exogenous or endocytic pathway of antigen processing in contrast to the endogenous or cytosolic pathway, which complexes the abnormal proteins produced within the cell (e.g.
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