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Chapter 34 : Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells

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Abstract:

Microorganisms maintain an evolutionary advantage over their slowly replicating eukaryotic hosts. High mutation rates, rapid doubling times, and free genetic exchange between microbial species often place a considerable burden on the infected host to counter virulence escape mechanisms. This selective pressure has driven the acquisition of numerous eukaryotic defense strategies to protect host genome integrity and promote survival at the level of the individual cell ( ). These cell-autonomous effector mechanisms, often considered unique to the immune cells of advanced metazoans, have in fact been largely inherited and repurposed from our eukaryotic ancestors ( Fig. 1 ). For example, phagocytosis developed as a trophic mechanism in unicellular amoebae long before its adaptation as a tool for immunity in the specialized “immune-like” cells of early invertebrates ( ). Amebocytes, hemocytes, and coelomocytes present in lower organisms likewise predate professional phagocytes in animals with their ability to bind, engulf, and kill foreign microorganisms ( ).

Citation: Gaudet R, Bradfield C, MacMicking J. 2017. Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells, p 615-635. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0050-2016
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Figure 1

Evolution of antimicrobial effector mechanisms. Depicted is a phylogenetic tree of the unikonts ( and ) and a summary of accompanying cell-autonomous effector mechanisms common to each major group. Scale indicates divergent nodal distance across NCBI taxa. Phylogram generated in Dendroscope 3.

Citation: Gaudet R, Bradfield C, MacMicking J. 2017. Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells, p 615-635. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0050-2016
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Figure 2

Canonical effector mechanisms in myeloid cells. (A) Enzymatically derived metabolites are potent antimicrobials. Macrophages deploy nutriprive mechanisms to reduce accessible nutrients and inhibit microbial growth, including NRAMP1 (SLC11A1), which pumps iron out of the phagosome; and IFN-γ-induced IDO1, which degrades intracellular tryptophan into kynurenine metabolites, which in themselves can be toxic to microbes. Superoxide generation by NOX2 and possibly DUOX1/2 generate ROS on the luminal side of the phagosome, which is directly antimicrobial. NO generation by NOS is also cytotoxic. Acidification by lysosomal V-ATPases or import of copper/zinc ions also functions to create a bactericidal environment within the phagosome. (B) AMPs are generated within the Golgi and trafficked to the pathogen-containing endosome. Here, they are processed into their active form to induce bacterial lysis. (C) Intracellular pathogens, either vacuolar or cytosolic, can become targeted by the autophagic machinery via host adaptor proteins that recognize signals of microbial infection. Proposed mechanisms include adaptors like p62/SQSTM1, which bind to ubiquitinated microbes or vacuoles; lectins like galectin 8 (LGALS8), which bind glycans exposed on damaged vacuoles; and TRIM21, which binds antibodies on the surface of incoming bacteria and viruses. These adaptors promote phagophore formation around their cargo by binding to autophagosome adaptor LC3. Microbes are then sequestered within the autophagosome, a process that requires the ATG proteins, and fuse with the lysosome for degradation.

Citation: Gaudet R, Bradfield C, MacMicking J. 2017. Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells, p 615-635. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0050-2016
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