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

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  • Authors: Ryan G. Gaudet1,2,3, Clinton J. Bradfield4,5,6, John D. MacMicking7,8,9
  • Editor: Siamon Gordon10
    Affiliations: 1: Howard Hughes Medical Institute, Chevy Chase, MD 20815; 2: Yale Systems Biology Institute; 3: Departments of Microbial Pathogenesis and Immunobiology, Yale University School of Medicine, New Haven, CT 06520; 4: Howard Hughes Medical Institute, Chevy Chase, MD 20815; 5: Yale Systems Biology Institute; 6: Departments of Microbial Pathogenesis and Immunobiology, Yale University School of Medicine, New Haven, CT 06520; 7: Howard Hughes Medical Institute, Chevy Chase, MD 20815; 8: Yale Systems Biology Institute; 9: Departments of Microbial Pathogenesis and Immunobiology, Yale University School of Medicine, New Haven, CT 06520; 10: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.MCHD-0050-2016
  • Received 17 September 2016 Accepted 20 October 2016 Published 16 December 2016
  • John D. MacMicking, [email protected]
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  • Abstract:

    Specialized adaptations for killing microbes are synonymous with phagocytic cells including macrophages, monocytes, inflammatory neutrophils, and eosinophils. Recent genome sequencing of extant species, however, reveals that analogous antimicrobial machineries exist in certain non-immune cells and also within species that ostensibly lack a well-defined immune system. Here we probe the evolutionary record for clues about the ancient and diverse phylogenetic origins of macrophage killing mechanisms and how some of their properties are shared with cells outside the traditional bounds of immunity in higher vertebrates such as mammals.

  • Citation: Gaudet R, Bradfield C, MacMicking J. 2016. Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells. Microbiol Spectrum 4(6):MCHD-0050-2016. doi:10.1128/microbiolspec.MCHD-0050-2016.


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Specialized adaptations for killing microbes are synonymous with phagocytic cells including macrophages, monocytes, inflammatory neutrophils, and eosinophils. Recent genome sequencing of extant species, however, reveals that analogous antimicrobial machineries exist in certain non-immune cells and also within species that ostensibly lack a well-defined immune system. Here we probe the evolutionary record for clues about the ancient and diverse phylogenetic origins of macrophage killing mechanisms and how some of their properties are shared with cells outside the traditional bounds of immunity in higher vertebrates such as mammals.

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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.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.MCHD-0050-2016
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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.

Source: microbiolspec December 2016 vol. 4 no. 6 doi:10.1128/microbiolspec.MCHD-0050-2016
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