Abstract
The soil-dwelling social amoeba Dictyostelium discoideum feeds on bacteria. Each meal is a potential infection because some bacteria have evolved mechanisms to resist predation. To survive such a hostile environment, D. discoideum has in turn evolved efficient antimicrobial responses that are intertwined with phagocytosis and autophagy, its nutrient acquisition pathways. The core machinery and antimicrobial functions of these pathways are conserved in the mononuclear phagocytes of mammals, which mediate the initial, innate-immune response to infection. In this review, we discuss the advantages and relevance of D. discoideum as a model phagocyte to study cell-autonomous defenses. We cover the antimicrobial functions of phagocytosis and autophagy and describe the processes that create a microbicidal phagosome: acidification and delivery of lytic enzymes, generation of reactive oxygen species, and the regulation of Zn2+, Cu2+, and Fe2+ availability. High concentrations of metals poison microbes while metal sequestration inhibits their metabolic activity. We also describe microbial interference with these defenses and highlight observations made first in D. discoideum. Finally, we discuss galectins, TNF receptor-associated factors, tripartite motif-containing proteins, and signal transducers and activators of transcription, microbial restriction factors initially characterized in mammalian phagocytes that have either homologs or functional analogs in D. discoideum.
Highlights
The mononuclear phagocyte system (MPS), comprising monocytes, macrophages, and dendritic cells, is the first line of defense against infection
We focus on the use of the soil dwelling, social amoeba Dictyostelium discoideum as a model phagocyte to study the interactions between intracellular pathogens and cell-autonomous defense mechanisms of MPS cells
Several D. discoideum mutants impaired in lysosomal enzyme trafficking and/or activity have been characterized including strains lacking WshA, a subunit of the WASH complex involved in lysosomal enzyme recycling [117], LvsB, a protein involved in restricting heterotypic fusion of early endosomes with postlysosomal compartments [145], and TM9 protein A, which is involved in the sorting of glycosidases, cathepsins, and lysozymes [146]
Summary
The mononuclear phagocyte system (MPS), comprising monocytes, macrophages, and dendritic cells, is the first line of defense against infection. We focus on the use of the soil dwelling, social amoeba Dictyostelium discoideum as a model phagocyte to study the interactions between intracellular pathogens and cell-autonomous defense mechanisms of MPS cells. Bacteria must contend with similar defense mechanisms in macrophages and amoebae; predation selects for bacterial survival strategies that are likely to resist killing by MPS cells [9,10,11,12].
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