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The regulation of phagosome maturation in Dictyostelium
1Department of Microbiology and Immunology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Abstract:
Macropinocytosis (fluid uptake) and phagocytosis (particle uptake) are processes that result in the formation of intracellular membrane enclosed vacuoles termed macropinosomes and phagosomes, respectively. Macropinosomes and phagosomes are modified by fission and fusion reactions with the endo-lysosomal pathway that eventually transform these vacuoles into a lysosomal environment. Many human bacterial pathogens, including species of Mycobacteria, Legionella, and Chlamydia, are thought to survive by disrupting the normal membrane trafficking events that usually result in the formation of phago-lysosomes and death of the microorganism. In addition, a number of important pathogens facilitate homotypic phagosome fusion in order to generate an intracellular environment conducive for survival. A greater understanding of the regulation of phagosomal maturation and fusion will be critical in designing new therapies to treat infections caused by intracellular pathogens. The genetically tractable phagocyte, D. discoideum, has proven extremely useful in dissecting the signaling pathways regulating macropinocytosis, phagocytosis, phagosomal maturation and phagosome-phagosome fusion. A body of knowledge has accumulated and demonstrates important roles for Rab GTPases, the cytoskeleton, phosphoinositide metabolism and pH regulation in regulating phagosome maturation. This review will summarize the current state of knowledge.
Insights
Understanding how pathogens disrupt phagosome maturation is key to developing new treatments. Research in Dictyostelium discoideum reveals critical roles for Rab GTPases, cytoskeleton, and phosphoinositides in phagosome fusion and survival.
Area of Science:
- Cell Biology
- Microbiology
- Immunology
Background:
- Macropinocytosis and phagocytosis generate intracellular vacuoles (macropinosomes and phagosomes).
- These vacuoles mature via fusion with the endo-lysosomal pathway, typically leading to microbial degradation.
- Many bacterial pathogens survive by interfering with phagosome maturation and fusion.
Purpose of the Study:
- To review the regulation of phagosomal maturation and fusion.
- To highlight the importance of understanding these processes for developing anti-infective therapies.
- To summarize current knowledge on the signaling pathways involved.
Main Methods:
- Review of existing literature on phagosome dynamics.
- Focus on studies utilizing the model organism Dictyostelium discoideum.
- Analysis of key molecular players like Rab GTPases and phosphoinositides.
Main Results:
- Phagosome maturation involves complex membrane trafficking, including fission and fusion events.
- Pathogens actively subvert these processes for intracellular survival.
- Homotypic phagosome fusion can be exploited by pathogens to create a niche.
Conclusions:
- Disrupting phagosome maturation is a common survival strategy for intracellular bacterial pathogens.
- Understanding the regulation of phagosome maturation and fusion is crucial for novel therapeutic strategies.
- Dictyostelium discoideum serves as a valuable model for dissecting these cellular processes.