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Antimicrobial Mechanisms of Phagocytes and Bacterial Evasion Strategies

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Antimicrobial Mechanisms of Phagocytes and Bacterial Evasion Strategies FOCUS ON MICROBIAL HOST CELL SUBREVIEWSVERSION Antimicrobial mechanisms of phagocytes and bacterial evasion strategies Ronald S. Flannagan*, Gabriela Cosío* and Sergio Grinstein 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. Endocytic pathway Professional phagocytes, such as macrophages, neu- summarize our current knowledge of phagocytosis and The route followed inside the trophils and dendritic cells, are uniquely qualified to describe salient examples of bacterial species that have cell by vesicles derived from engulf large (≥ 0.5 μm) particles, including microorgan- evolved distinct strategies to evade killing. the plasma membrane by isms. The internalization and subsequent destruction endocytosis, including their Phagosome formation membrane-associated cargo of pathogens are key to the innate immune response, and trapped fluid. Vesicles or and promote antigen presentation and the develop- The interaction of the microorganism with the phago- vacuoles derived from the ment of adaptive immunity. After engulfment, the cyte can be direct, through recognition of pathogen- plasma membrane undergo microorganisms are trapped, together with extracellu- associated molecules (such as surface carbohydrates, fusion and fission events that lar fluid, in a vacuole, or phagosome, derived from the peptidoglycans or lipoproteins) by pattern recognition deliver some of their components to lysosomes for plasma membrane. Because the nascent phagosomal receptors, or indirect, through mediation by opsonins. degradation, whereas others membrane and its contents are innocuous, they must Opsonins are host factors, such as immunoglobulin G are recycled. undergo a drastic conversion to acquire the microbi- (IgG), and components of the complement cascade that cidal and degradative features associated with innate attach to the pathogen surface, acquiring a conforma- immunity. This conversion, known as phagosomal tion that is recognized by phagocytic receptors, such maturation, is accomplished through a strictly cho- as Fcγ receptors (FcγRs) and complement receptor 3 reographed sequence of fusion and fission events that (CR3)1. The signalling that is triggered by the particle involve defined compartments of the endocytic pathway varies depending on the nature of the receptors engaged. (FIG. 1). Effective phagocytosis therefore requires two The pathway elicited by FcγR is best understood. components: particle internalization and phagosomal Exposure to multivalent ligands induces clustering of maturation. these receptors in the plane of the membrane, initiating Although most bacteria are successfully internal- phosphorylation of their cytoplasmic immunoreceptor ized and eliminated by phagocytes, several patho- tyrosine-based activation motifs (ITAMs) by Src-family Program in Cell Biology, 2 The Hospital for Sick Children, gens have developed survival strategies that interfere kinases . ITAM phosphorylation recruits and activates 555 University Avenue, with the internalization and/or maturation processes. the tyrosine kinase SYK, which in turn phosphorylates Toronto, Ontario M5G 1X8, Prevention and management of the infections caused various substrates3. The events that follow SYK activa- Canada. by such pathogens would obviously benefit from tion and culminate in particle engulfment are not as Correspondence to S.G. understanding the manner in which they circum- clearly understood. Remodelling of actin is unambigu- e-mail: [email protected] *These authors contributed vent and often co-opt the immune response. This, in ously required for pseudopod extension and, in the equally to this work. turn, requires detailed knowledge of the basic mecha- case of FcγR, polymerization is driven by Rac1 and/ doi:10.1038/nrmicro2128 nisms underlying phagocytosis. To this end, we briefly or Rac2, and cell division control protein 42 (Cdc42)4. NATURE REVIEWS | MICROBIOLOGY VOLUME 7 | MAY 2009 | 355 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS Early endosome Multivesicular body Late endosome Lysosome a Early b Intermediate c Late d Phagolysosome VPS34 LAMP1 Rab7 LAMP1 PI(3)P ESCRT Cathepsins EEA1 Hydrolases Rab5 Bacterium Bacterium Bacterium Bacterium RABEX LBPA PI(3)P LAMP2 CD63 LBPA RILP V-ATPase HOPS Rab5 LAMP2 Cathepsins Microtubules Hydrolases Dynein or dynactin MHC II Recycling endosome Trans-Golgi network presentation pH 7.4 4.5 Figure 1 | Stages of phagosomal maturation. Shortly after pathogen uptake, the phagosomeNatur undergoese Reviews a| Micr seriesobiolog of y transformations that result from its sequential interaction with subcompartments of the endocytic pathway. Different stages of maturation are recognized — early (a), intermediate (b) and late (c) phagosomes — that culminate with the formation of phagolysosomes (d). During maturation, the phagosomes acquire various hydrolases and undergo a progressive acidification caused by proton pumping by the V-ATPase. EEA1, early endosome antigen 1; ESCRT, endosomal-sorting complex required for transport; HOPS, homotypic protein sorting; LAMP, lysosomal-associated membrane protein; LBPA, lysobisphosphatidic acid; PI(3)P, phosphatidylinositol-3-phosphate; MHCII, major histocompatibility complex II; RILP, Rab-interacting lysosomal protein. The identity of the guanine nucleotide exchange fac- area. Paradoxically, capacitance measurements have tors (GEFs) that are responsible for Rac and Cdc42 shown that the plasmalemmal surface in fact increases activation are the subject of debate5,6. By contrast, it is during phagocytosis14. This has been attributed to focal generally agreed that downstream effectors, such as exocytosis of endomembranes at sites of phagocyto- Wiskott–Aldrich syndrome protein7, which in turn sis. Recycling15 and late endosomes16 are thought to be interacts with and activates actin-related protein 2/3 the main contributors, but even lysosomes have been (Arp2/3), are actively involved in actin polymerization reported to fuse when the demand for membrane is during FcγR-initiated phagocytosis8. In the case of CR3- excessive17,18. Rab and ADP-ribosylation factor (Arf) mediated phagocytosis, the diaphanous-related formin GTPases are thought to be important in directing Dia1 (also known as DIAPH1) is thought to initiate and tethering the endomembrane organelles to form actin filament nucleation and elongation4,9. phagosomes19,20, whereas SNARE proteins (soluble NSF- Phosphoinositides also provide an important contri- attachment protein receptor proteins), including vesicle- bution to actin remodelling during phagocytosis. Both associated membrane protein 3 (VAMP3)15 and VAMP7 Phosphoinositide (REF. 16) An inositol phospholipid that phosphatidylinositol-4,5-bisphosphate and phosphati- underpin the fusion reaction. can be phosphorylated dylinositol-3,4,5-trisphosphate accumulate at sites of separately or at all possible particle engagement and are instrumental in timing Phagosome maturation combinations of the D-3, D-4 the onset and termination of actin assembly. Whereas Maturation starts immediately after, and possibly even and D-5 positions of the phosphatidylinositol-4,5-bisphosphate is essential before, phagosome sealing. After scission from the sur- inositol ring. for the initial polymerization that drives pseudopod face membrane, the phagosome undergoes sequential SNARE protein formation, its conversion to phosphatidylinositol- fusion with early endosomes, late endosomes and lyso- A member of the soluble 3,4,5-trisphosphate seems to be required for pseudo- somes21. Whether complete fusion of the incoming mem- N-ethylmaleimide sensitive pod extension and phagosomal closure10, at least in branes with the pre-existing vacuole or ‘kiss and run’ factor attachment protein 11 receptor family that mediates part by recruitment of myosin X . The metabolism events are involved remains unclear and a combination docking and fusion of cellular of other phospholipids by phospholipases A and D is of both may occur. Regardless, remodelling of the mem- membranes. Cognate SNARE also necessary for successful completion of phagocyto- brane of the phagosome is accompanied by acute changes pairs on the vesicular and sis12,13, although the precise products and mechanisms in the composition of its lumen, which becomes a highly target membranes intertwine involved have not been fully resolved. acidic, oxidative and degradative milieu. The steps lead- to form a SNARE pin that brings the membranes into During phagocytosis of large or multiple particles, ing to the formation of the phagolysosome, which is the close apposition, driving their a considerable amount of membrane is internalized, terminal stage of the maturation sequence, are illustrated fusion. and the cell needs to compensate for the loss of surface in FIG. 1 and discussed in more detail below. 356 | MAY
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