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Antimicrobial mechanisms of phagocytes and bacterial evasion strategies

Key Points

  • The innate immune response constitutes the first line of defence against pathogenic microorganisms.

  • Phagocytes, such as macrophages and neutrophils, engulf microorganisms into a vacuole or phagosome that is gradually converted into an effective microbicidal organelle.

  • Such remodelling of the phagocytic vacuole, a process known as maturation, occurs by coordinated fission and fusion events involving multiple subcompartments of the endocytic pathway.

  • Phagosome maturation is directed by small GTPases, requires SNARE (soluble NSF-attachment protein receptor) proteins and involves extensive lipid remodelling of the vacuolar membrane.

  • A number of intracellular pathogens have evolved strategies to arrest or divert phagosome maturation, or can escape the confines of the phagocytic vacuole.

  • We discuss examples of bacterial effectors that are injected into the host cells and cause disruption of the maturation pathway, often by co-opting the host cell machinery, to generate a niche conducive to bacterial survival and replication.

Abstract

Professional phagocytes have a vast and sophisticated arsenal of microbicidal features. They are capable of ingesting and destroying invading organisms, and can present microbial antigens on their surface, eliciting acquired immune responses. To survive this hostile response, certain bacterial species have developed evasive strategies that often involve the secretion of effectors to co-opt the cellular machinery of the host. In this Review, we present an overview of the antimicrobial defences of the host cell, with emphasis on macrophages, for which phagocytosis has been studied most extensively. In addition, using Mycobacterium tuberculosis, Listeria monocytogenes, Legionella pneumophila and Coxiella burnetii as examples, we describe some of the evasive strategies used by bacteria.

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Figure 1: Stages of phagosomal maturation.
Figure 2: The microbicidal arsenal of phagocytes versus the defensive mechanisms of the microorganism.
Figure 3: Strategies used by professional intracellular bacterial pathogens to modulate phagosome maturation.

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Acknowledgements

Work in the authors' laboratory is supported by the Canadian Cystic Fibrosis Foundation, the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research (CIHR). R.S.F. is supported by a CIHR Fellowship and G.C. is supported by the National Council of Science and Technology of Mexico (CONACYT).

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DATABASES

Entrez Genome Project

Coxiella burnetii

Legionella pneumophila

Listeria monocytogenes

Mycobacterium tuberculosis

Glossary

Endocytic pathway

The route followed inside the cell by vesicles derived from the plasma membrane by endocytosis, including their membrane-associated cargo and trapped fluid. Vesicles or vacuoles derived from the plasma membrane undergo fusion and fission events that deliver some of their components to lysosomes for degradation, whereas others are recycled.

Phosphoinositide

An inositol phospholipid that can be phosphorylated separately or at all possible combinations of the D-3, D-4 and D-5 positions of the inositol ring.

SNARE protein

A member of the soluble N-ethylmaleimide sensitive factor attachment protein receptor family that mediates docking and fusion of cellular membranes. Cognate SNARE pairs on the vesicular and target membranes intertwine to form a SNARE pin that brings the membranes into close apposition, driving their fusion.

Multivesicular body

(MVB). A defined stage in the transit between early endosomes and late endosomes or lysosomes. MVBs are characterized by a limiting membrane that encloses internal vesicles rich in lysobisphosphatidic acid, CD63 and phosphatidylinositol-3-phosphate. Proteins destined for degradation are sorted to internal vesicles of MVBs.

Azurophil or primary granule

A specialized neutrophil granule, also called a peroxidase-positive granule, that resembles lysosomes, in that it contains degradative enzymes, such as β-glucuronidase, cathepsins, elastase, lysozyme and myeloperoxidase, as well as antimicrobial peptides, such as defensins.

Specific or secondary granule

A specialized neutrophil granule, also called a peroxidase-negative granule, that exists as a heterogeneous continuum of granules with varying amounts of lactoferrin, collagenase, heparanase, lysozyme and antimicrobial cathelicidins.

Autophagy

A complex cellular process by which intracellular components, including entire organelles, are sequestered in double-membrane vesicles or vacuoles called autophagosomes that eventually fuse with lysosomes, bringing about the degradation of their contents.

SarI–COPII-coated secretory vesicle

A vesicle derived from the endoplasmic reticulum (ER) through coating with the coatomer protein complex II (COPII) protein complex, a process initiated at specialized ER exit sites by the GTPase SarI.

Type IV secretion system

A macromolecular apparatus used by bacteria to secrete effector molecules. This secretion system is ancestrally related to bacterial DNA conjugation systems, and is often expressed by pathogenic bacteria, which contributes to their virulence.

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Flannagan, R., Cosío, G. & Grinstein, S. Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nat Rev Microbiol 7, 355–366 (2009). https://doi.org/10.1038/nrmicro2128

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