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Receptor-Mediated Phagocytosis of Leishmania: Implications For Review Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival 1 1,2,3 Norikiyo Ueno and Mary E. Wilson 1 Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA 2 Departments of Internal Medicine and Epidemiology, University of Iowa, Iowa City, IA 52242, USA 3 Veterans’ Affairs Medical Center, Iowa City, IA 52246, USA The extracellular promastigote stage of Leishmania Glossary spp. is transmitted to mammals by a sand fly vector. Amastigote: the aflagellated form of Leishmania spp. parasites that resides Leishmania promastigotes ligate host macrophage intracellularly within vertebrate host cells. receptors, triggering phagocytosis and subsequent in- COS cells: an African green monkey kidney cell line, with the name derived from ‘being CV-1 in origin’, carrying portions of the SV40 genome. ternalization, a crucial step for survival. Parasites trans- DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing form intracellularly to the amastigote stage. Many nonintegrin): a receptor for mannosylated glycoconjugates that is found on studies document different receptors detecting pro- macrophages and mature dendritic cells. DC-SIGN has been implicated in pathogen recognition as well as leukocyte adhesion via attachment to mastigotes and amastigotes, but the relative impor- intercellular adhesion molecules (ICAM)-2 and -3. tance of each interaction is ill-defined. Recent studies Fc gamma receptors: receptors on the surface of phagocytes, including suggest that the macrophage receptors utilized during macrophages and neutrophils, that bind to the Fc fragment of immunoglobulin G and stimulate the phagocytosis of particles attached to the antibodies. phagocytosis impact the intracellular fate of the para- Fibronectin receptors: integrins on the surface of a variety of cell types, such as site. This review summarizes the receptors implicated in phagocytes and fibroblasts, which bind to fibronectin, an abundant glycopro- Leishmania phagocytosis over the past 30 years. It then tein in the extracellular matrix that mediates tissue connectivity. CR1 (first complement receptor): a receptor on the surface of phagocytes, proceeds to weigh the evidence for or against their including macrophages and neutrophils, that bind predominantly to C3b and potential roles in intracellular parasite trafficking. C4b proteins of the complement cascade, facilitating clearance of particles opsonized by these proteins via phagocytosis. GP63 (glycoprotein 63): the major metalloprotease that is abundantly Macrophage receptors implicated in Leishmania expressed on the surface of virulent Leishmania promastigotes. When phagocytosis promastigotes are opsonized by C3b, GP63 cleaves this to iC3b, which More than 20 species of Leishmania cause symptomatic facilitates promastigote recognition by CR3. GP63 is also called leishmanoly- sin, PSP (promastigote surface protease) or MSP (major surface protease). leishmaniasis in over 12 million people, with disease se- Ligate/ligation: specific binding of receptors on the host cell with their verity ranging from cutaneous ulcerations to fatal visceral appropriate antigen on the surface of pathogens. infections [1]. Leishmania are found in several mammalian Lipophosphoglycan (LPG): a Leishmania surface antigen that densely coats the surface of promastigotes. LPG is attached to the parasite surface by a cells, but the majority of parasites reside in macrophages glycoinositide anchor. A phosphodiester bond links to the anchor an extended [2,3]. The promastigote stage of Leishmania ligates mac- polysaccharide backbone, ‘capped’ by terminal sugar residues that vary between different Leishmania spp. rophage surface receptors that trigger phagocytosis. This is Mannose receptor (MR): a C-type lectin carbohydrate binding protein that followed by parasite transformation to the obligate intra- serves as a broad-range pattern recognition receptor via detection of mannose cellular amastigote stage. Receptors reported to facilitate on the surface of pathogens. MR is predominantly expressed in macrophages but is also found on neutrophils and dendritic cells. Leishmania internalization include the third complement Metacyclic promastigotes: the virulent form of Leishmania promastigotes that receptor (CR3) (see Glossary), first complement receptor arise following metacyclogenesis, a developmental process that occurs as the (CR1), mannose receptor (MR), Fc gamma receptors parasites move progressively from the midgut to the foregut and proboscis of the sand fly insect vector. (FcgRs, in particular FcgRII-B2), and fibronectin receptors Opsonin: proteins or protein complexes that bind to antigens on the surface of (FnRs) (Table 1) [4–8]. A definitive understanding of the foreign particles. Opsonins form part of the innate immune response of the roles of various receptors in parasite survival during nat- host. Receptors on immune cells then bind to opsonins, resulting in indirect detection of pathogens. ural infection has remained elusive [9,10]. The mechanism Phagolysosome: a pathogen-containing compartment that develops within of macrophage entry reflects, in part, the dynamic nature of phagosomes following a series of fusion events with endosomal and the parasite surface. The most abundant surface mem- lysosomal organelles. A fully mature phagolysosome is a hostile environment for intracellular organisms that are unfit to evade the parasitophorous vacuole. brane components differ between the extracellular pro- Promastigote: the flagellated form of Leishmania that exists extracellularly in mastigote form found in insects and the intracellular the sand fly insect vector. amastigote form found in mammals [11]. Metacyclogen- Pseudopod: protrusions of the macrophage membrane that is the result of extensions of actin filaments near the edges of the cell. esis, the developmental process leading promastigotes to Third complement receptor (CR3): an integrin on the surface of phagocytes, including macrophages and neutrophils that primarily detect iC3b during pathogen recognition. The role of CR3 is varied, and encompasses particle Corresponding author: Wilson, M.E. ([email protected]). clearance, leukocyte adherence, and actin reassembly. Keywords: Leishmania; promastigote; amastigote; metacyclic promastigote; U937 cells: an immortalized monocyte-like cell line of human origin. U937 cells macrophage; phagocytosis; parasitophorous vacuole; receptor; CR1; CR3; DC-SIGN; can be stimulated to differentiate Fc receptor; fibronectin receptor; mannose receptor. 1471-4922/$ – see front matter . Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.pt.2012.05.002 Trends in Parasitology, August 2012, Vol. 28, No. 8 335 Review Trends in Parasitology August 2012, Vol. 28, No. 8 Table 1. Receptors for Leishmania phagocytosis a b c d e Receptor, host cell type Cooperation Life stages Binding mechanism Functional consequences CR3 [6,11,31,34,35,42] CR1 [44] Avirulent PM: Direct: CR3-mediated phagocytosis (CD11b/CD18) L. major L. amazonensis Unknown ligand binds alternate lectin-like recruits Rho GTPase for Primary MF: MR [10,34] L. i. chagasi binding site of CR3 (L. infantum) [4,7,34] cytoskeletal rearrangement [67] BMM, MDM, MPM L. donovani L. donovani PSA-2 binds CD11b subunit Ligation of CR3 by iC3b inhibits Cell lines: J774A.1, THP-1, L. i. chagasi L. infantum (L. infantum) IFN-g mediated proinflammatory COS + CR3, 293 + CR3 FnRs [49,55,56] L. major [35] signaling, downregulating Other: L. amazonensis L. Mexicana iC3b-mediated: H2O2 and IL-12 production [69] PMN FcgRs [6] Metacyclic PM: Opsonized C3b from serum is converted PVs formed after CR3-mediated L. mexicana L. i. chagasi by CR1 and factor I into iC3b, a uptake are tight fitting [2] L. infantum CR3 a-chain ligand (all spp.) Phagolysosome maturation is L. major [4,31,33,34,44] delayed. LAMP-1 and cathepsin-D Amastigote: accumulation is impaired [10,28] L. amazonensis L. donovani L. major L. mexicana CR1 [5,44] CR3 [44] Avirulent PM: C3b-mediated: CR1 likely functions to enhance (CD35) L. major L. amazonensis Opsonized C3 from serum is cleaved by CR3 ligation [44,71] CR1 signaling Primary MF: L. major GP63 into C3b, the natural ligand for by Leishmania spp. may not MDM Metacyclic PM: CR1 (L. major) [24] trigger respiratory burst [5] Cell lines: L. major CHO + CR1 MR [4,9,10,34] CR3 [10,34] Avirulent PM: Direct: Signaling depends on MF (CD206) L. donovani L. i. chagasi Mannan-capped LPG backbone and side activation state [78,79,83] Primary MF: L. donovani chains possibly bind the CRD4 and CRD5 MR can trigger synthesis of – BMM, MDM, MPM domains of MR (L. chagasi, L. donovani) TNF-a, O2 and lysosomal [26,27,78] enzymes [80–82] Virulent parasites avoid MR ligation Lysosomal fusion can be (L. chagasi, L. donovani, L. major) [9,10,48] prevented by inhibiting tyrosine kinase Hck recruitment [84] MR inhibits IL-12 production [85] FnRs [8,49,50] CR3 [49,55,56] Avirulent PM: Direct: Internalization via FnRs requires (CD49d.CD29, L. amazonensis L. amazonensis a4 subunit of ‘fibroblast-origin’ FnR binds intact b1 subunit [49] CD49e/CD29, L. major L. major to a non-RGDS motif of GP63 Activation of CR3 by FnR is CD41/CD61) L. infantum L. infantum (L. amazonensis) [49,52] required for CR3-bound particle Primary MF: Amastigotes: Fibronectin-mediated: ingestion [38] MDM, MPM, L. amazonensis Nonspecific opsonization by serum FnR-mediated phagocytosis À Human monocytes fibronectin allows FnRs to detect RGDS generates O2 [51] Cell lines: and EILDV motifs PM can shed
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