The phagolysosome is a cellular compartment that results from the fusion of a phagosome with a lysosome, in the absence of autophagy; although the phagosome could also fuse to an endosome, prior to fusion with the lysosome.
The phagosome is a compartment surrounded by a single membrane, which is formed as a result of phagocytosis. The newly formed phagosome undergoes a process called maturation, which involves its fusion to lysosomes. This phenomenon produces a mature phagolysosome, whose interior is acidic and highly hydrolytic.
Source: GrahamColm at English Wikipedia
Cells specialized in phagocytosis, such as macrophages and neutrophils, destroy pathogens entered the cell and secrete pro-inflammatory cytokines. These examples highlight the importance of phagolysosomes.
characteristics
Phagolysosomes are characterized by the following:
- They have an acid pH (around pH 5). Similar to lysosomes and endosomes, pH is regulated through the ATPase-V proton pump complex. Acidic pH creates an inhospitable environment for pathogens, favors superoxide dismutation, and is the optimal pH for hydrolytic enzymes.
The pH within phagolysosomes has been determined by different methods. One of them consists of using dyes such as acridine orange, whose fluorescence depends on the pH.
- High hydrolytic activity of enzymes that degrade proteins (cathepsins), lipids and sugars (beta-galactosidase). For example, in macrophages, lysozyme helps degrade the peptidoglycan backbone of bacteria.
One method of detecting enzyme activity consists of labeling particles, which will be phagocytosed, with a substrate that changes their fluorescent properties after catalysis. This method is used to measure oxygen free radicals (ROS).
- Explosion of superoxide activity. NADPH oxidase participates in the formation of superoxide radicals (O 2 • -), which are transformed into hydrogen peroxide (H 2 O 2) by superoxide dismutase.
Also, superoxide combines with nitric oxide and forms peroxynitrite, which has antimicrobial activity.
Biogenesis
Mammalian cells possess a large number of cell types that perform phagocytosis. This process begins with the interaction of the ligand on the surface of the receptor. The ligand can be a bacterium or an apoptotic cell. The receptor bound to the ligand is internalized in the form of a vesicle, called a phagosome.
Internalization requires kinase activation and alteration of phospholipid metabolism, among other events. However, the phagosome does not degrade the ligand. The endowment of lytic activity to the phagosome depends on its interaction with lysosomes.
Experimental evidence indicates that newly formed phagosomes, termed early phagosomes, preferentially interact with endosomes. Phagosomes express signals that trigger and guide their fusion to elements of the endocytic pathway.
Proof of this is that early phagosomes contain components of the plasma membrane and proteins typical of endosomes, such as transferrin receptors (TfRs), EEA1, Rab5, Rab 7.
The fusion of early phagosomes with lysomes can be confirmed by their protein composition. In this case, the phagolysomes have the LAMP and cathepsin D proteins.
The regulation of phagosome maturation is complex and depends on guanine nucleotide exchange proteins (GEF), GTP hydrolyzing proteins (GAP), among other effectors.
Features
Phagocytes, or cells that make phagocytosis, are classified as low (non-professional), medium (para-professional), and high (professional) phagocytic competence phagocytes. Neutrophils and macrophages are professional phagocytes of the immune system.
These phagocytes are responsible for trapping and destroying apoptotic host cells, contaminating particles, and organisms with pathogenic potential.
Neutrophils and macrophages kill phagocytosed microbes. The death of microbes is carried out through a sequence of steps, which are the following:
- Activation of proteolytic enzymes, such as elastase. This last enzyme is a serine protease, involved in the death of many types of bacteria. Another protein involved is cathepsin G.
- Activation of the phagocyte oxidase system, which is a multimeric enzyme found in the phagolysosome membrane. Phagocyte oxidase is induced and activated by stimuli, such as IFN-gamma and TLR signals. This enzyme reduces ROS using NADPH as an electron donor substrate.
- Macrophages produce nitric oxide through inducible nitric oxide synthase. This enzyme catalyzes the conversion of arginine to citrulline and nitric oxide, which reacts with superoxide to form peroxynitrile, a powerful poison that kills microbes.
Diseases
There is a growing interest in studying genetic diseases related to defects in phagocytosis. In addition to this interest, concerns have been raised about antibiotic resistance in bacteria, which have ways of preventing death within phagocytes.
Therefore, the study of the immune system and its interaction with pathogenic microbes will allow the development of new antimicrobial strategies.
Chronic granulomatous disease
Chronic granulomatous disease (CGD) is due to an immunodeficiency that causes patients to frequently suffer from infections, caused by bacteria and fungi. The most common microbes are Staphylococcus aureus, and species of the genera Aspergillus, Klebsiella, and Salmonella.
Symptoms
Patients with CGD present an inflammatory condition, characterized by the presence of granulomas, colitis, non-infectious arthritis, osteomyelitis, and peri-rectal access, among other symptoms.
Inflammation is caused by a deficiency in autophagic defense against microbes. Consequently, IL-1beta is released and T cell regulation is poor.
CGD occurs as a result of the deficiency of the enzyme NADPH oxidase in leukocytes. NADPH oxidase has five components (gp91, p22, p47, p67 and p40). The most common mutation is in the CYBB gene, which codes for gp91.
A less frequent mutation occurs in the NCF1 gene, which codes for p47, and the rarest mutation occurs in the NCF2 gene, which codes for p67.
Treatment
The disease is usually treated with antibiotics and antifungals. Treatment against gram-negative bacteria includes a combination of ceftazidime and carbapene. While fungi are treated with oral triazoles, such as itraconazole and posaconazole.
During infection-free periods, the use of trimethopin-sulfamethoxazole together with an antifungal such as itraconazole is recommended.
References
- Abbas, AK, Lichtman, AH and Pillai, S. 2007. Cellular and Molecular Immunology. Saunders Elsevier, USA.
- Kinchen, JK & Ravichandran, KS 2008. Phagosome maturation: going through the acid test. Natural Review Molecular Cell Biology, 9: 781–795.
- Klionsky, DJ, Eskelinen, EL, Deretic, V. 2014. Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes… Wait, I'm confused. Autophagy, 10: 549–551.
- Roos, D. 2016. Chronic granulomatous disease. British Medical Bulletin, 118: 53–66.
- Russell, D., Glennie, S., Mwandumba, H., Heyderman, R. 2009. The macrophage marches on its phagosome: dynamic assays of phagosome function. Natural Review Immunology, 9: 594–600.
Vieira, OV, Botelho, RJ Grinstein, S. 2002. Phagosome maturation: aging gracefully. Biochemestry Journal, 366: 689-704.