Nonopsonic Phagocytosis of Erythrocytes Infected with Ring-Stage Plasmodium falciparum
http://www.100md.com
感染与免疫杂志 2005年第4期
Department of Medicine
McLaughlin-Rotman Center for Global Health, McLaughlin Center for Molecular Medicine, University of Toronto
Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada
ABSTRACT
Ring-stage parasitized erythrocytes (RPEs) were demonstrated to interact with effector cells of the innate immune system. With receptor blockade studies and CD36-null macrophages, human and murine macrophages were shown to phagocytose RPEs through the pattern recognition receptor CD36. These in vitro data implicate scavenger receptors in the clearance of RPEs.
TEXT
Phagocytic clearance of Plasmodium falciparum-parasitized erythrocytes (PEs) is an important line of innate defense against malaria (20, 25). Pattern recognition receptors, including CD36, have been implicated in innate clearance of mature-stage PEs (MPEs) by monocytes and macrophages (3, 12, 13, 15, 21, 22, 24, 26). Ring-stage PEs (RPEs) have recently been shown to express ligands capable of interacting with endothelial cells (5, 16, 23, 29). The objective of this study was to examine whether RPEs might also interact with effector cells of the innate immune system.
We demonstrate that murine and human monocyte-derived macrophages can recognize and phagocytose RPEs (see Fig. 1 to 3). To ensure that only ring-stage parasites were used in phagocytosis assays (15, 21), we used procedures (2, 10) to generate highly synchronous ring-stage cultures (purity, >99% RPEs) and used cryopreserved malaria isolates and fresh clinical isolates that only contained RPEs (confirmed by microscopic criteria) (see Fig. 4). To ensure that only RPEs were quantified in phagocytic assays, we used a strict lysis procedure to remove adherent erythrocytes and morphological criteria (12, 23) to ensure that only phagocytosed PE were counted. The slides were read blinded to the experimental conditions and confirmed by a second reader.
To investigate the molecular mechanisms underlying RPE phagocytosis, we undertook receptor blockade studies with monoclonal antibodies (MAbs) against macrophage receptors known to interact with PEs and against macrophage pattern recognition receptors (4, 9) (Fig. 1). Only CD36 receptor blockade resulted in a significant decrease in RPE or MPE phagocytosis. Inhibition of phagocytosis was confirmed with two separate parasite lines: 3D7 (30) and ITG (17).
To confirm the role of CD36 in mediating RPE uptake, we examined phagocytosis by CD36 wild-type and CD36-null macrophages (7, 15). Phagocytosis of RPEs was reduced by 90% in CD36-null macrophages. To investigate whether other macrophage receptors might cooperate with CD36 or mediate uptake in the absence of CD36 (1, 6, 14, 18, 19, 28, 29), we performed phagocytosis assays with wild-type and CD36-null macrophages in the presence of MAbs to other macrophage surface receptors. MAb blockade of receptors other than CD36 did not significantly decrease uptake of RPEs (Fig. 2A). Since pattern recognition receptors such as the mannose receptor have also been implicated in opsonin-independent phagocytosis of P. chabaudi (26), we investigated whether the mannose receptor contributed to RPE uptake. As shown in Fig. 2A, mannan did not significantly decrease uptake of RPEs but did inhibit uptake of MPEs compared to -glucan treatment (data not shown).
Adhesion of MPEs to CD36 is primarily mediated by PfEMP-1. PfEMP-1 is removed from the surface of PEs following mild protease treatment, and cleaving this ligand has been shown to decrease macrophage uptake of MPEs (12, 15, 21). Cytoadhesion of RPEs to endothelial cells has also been reported to be protease sensitive (16). We investigated whether the phagocytosis of RPEs is also dependent upon protease-sensitive ligands on RPEs. Cleavage of surface ligands from RPEs with trypsin reduced the phagocytic clearance of RPEs to the level observed with CD36-null macrophages (Fig. 2B).
The CD36 gene promoter contains a response element recognized by the nuclear receptor heterodimer PPAR-RXR (8, 27), and PPAR-RXR agonists increase CD36 expression and uptake of MPEs (15, 21, 22). We tested the hypothesis that PPAR agonists would increase macrophage uptake of RPEs by upregulating CD36 or other macrophage pattern recognition receptors. Phagocytosis of synchronized RPEs (Fig. 3) or RPEs from cryopreserved or fresh clinical isolates (Fig. 4) was significantly increased by pretreatment of macrophages with PPAR agonists. The increased uptake appeared to be CD36 dependent since it was eliminated by CD36 receptor blockade.
RPE adhesion has been reported in parasites that subsequently acquire the chondroitin sulfate A (CSA)-binding phenotype (16). We examined phagocytosis of RPEs from parasite lines E8B, which binds to CD36, and CS2, which binds to CSA. The uptake of CS2 RPEs was significantly lower than that of E8B RPEs (Fig. 5).
Increasing evidence indicates that innate immune responses contribute to the control of blood-stage malaria infection, lighten the parasite burden, and decrease progression to severe disease (25). In this study, we examined the ability of RPEs to interact with effector cells of the innate immune system. We present evidence that ligands expressed by RPEs confer the capacity for recognition and uptake by macrophages. We demonstrate that human monocyte-derived macrophages and murine macrophages are able to phagocytose RPEs in vitro even in the absence of opsonization and in the presence of an Fc receptor blockade. A role for the scavenger receptor CD36 in mediating nonopsonic phagocytosis of RPEs was supported by the observations that uptake was inhibited by a CD36 blockade, by the cleavage of putative CD36 ligands from the RPEs, and by the elimination of uptake of RPEs by CD36-null macrophages. Furthermore, RPE uptake was significantly increased by cotreatment with the PPAR agonists, which upregulate surface levels of CD36. These data suggest that nonopsonic uptake in vitro appears to be largely dependent on CD36 and not on other macrophage receptors such as ICAM-1, v3, or PECAM-1 or pattern recognition receptors such as the mannose receptor or CD14. These observations are similar to those reported for uptake of MPEs by macrophages (12, 15, 21); however, different surface ligands may interact with CD36 in these cases. For MPEs, previous studies suggest that PfEMP-1 is the primary ligand interacting with CD36 (12, 15, 21). RPEs may express one or more surface ligands capable of interacting with CD36. Pouvelle and colleagues (16) have shown that RPE can adhere to an unknown receptor on syncytiotrophoblast and endothelial cells. Adhesion was dependent upon the presence of a parasite rhoptry-derived ring surface protein, RSP-2 (5). Their studies indicate that RSP-2 appears earlier on malaria-infected erythrocytes than does PfEMP-1, but both ligands may be simultaneously present on the same erythrocyte. In contrast, Udomsangpetch and colleagues attributed RPE cytoadherence to PfEMP-1 (29). The var genes that encode PfEMP-1 have been shown to be expressed as early as 3 h after merozoite invasion (11). Recent data indicate that PfEMP-1 is expressed in RPEs and that trafficking to the membrane is facilitated at elevated temperatures (29). Additional study is required to better characterize the RPE ligand(s) that interacts with CD36.
In summary, our data indicate that the scavenger receptor CD36 participates in clearance of RPEs in vitro and may contribute to innate control of blood-stage infection; however this will require confirmation in vivo.
ACKNOWLEDGMENTS
This work was supported by Canadian Institutes of Health Research (CIHR) operating grant MT-13721 (K.C.K.), a CIHR Canada Research Chair (K.C.K.), and a CIHR fellowship (L.S.).
REFERENCES
1. Berendt, A. R., D. L. Simmons, J. Tansey, C. K. Newbold, and K. Marsh. 1989. Intercellular adhesion molecule 1 (ICAM-1) is an endothelial cytoadherence receptor for Plasmodium falciparum. Nature 341:57-59.
2. Brau-Breton, C., T. L. Rosenberry, and L. H. Pereira da Silva. 1988. Induction of the proteolytic activity of a membrane protein in Plasmodium falciparum by phosphatidyl inositol-specific phospholipase C. Nature 332:457-459.
3. Chuluyan, H. E., and A. C. Issekutz. 1993. VLA-4 can mediate CD11/CD18-independent transendothelial migration of human monocytes. J. Clin. Investig. 92:2768-2777.
4. Deitsch, K. W., and T. E. Wellems. 1996. Membrane modifications in erythrocytes parasitized by Plasmodium falciparum. Mol. Biochem. Parasitol. 76:1-10.
5. Douki, J. B., Y. Sterkers, C. Lepolard, B. Traore, F. T. Coasta, A. Scherf, and J. Gysin. 2003. Adhesion of normal and Plasmodium falciparum ring-infected erythrocytes to endothelial cells and the placenta involves the rhoptry-derived ring surface protein-2. Blood 101:5025-5032.
6. Fadok, V. A., M. L. Warner, D. L. Bratton, and P. M. Henson. 1998. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (v3). J. Immunol. 161:6250-6257.
7. Febbraio, M., N. A. Abumrad, D. P. Hajjar, K. Sharma, W. Cheng, S. F. A. Pearce, and R. L. Silverstein. 1999. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274:19055-19062.
8. Gearing, K. L., M. Gottlicher, M. Teboul, E. Widmark, and J. A. Gustafsson. 1993. Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc. Natl. Acad. Sci. USA 90:1440-1444.
9. Hoffmann, P. R., A. M. deCathelineau, C. A. Ogden, et al. 2001. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Biol. Chem. 155:649-659.
10. Kutner, S., W. V. Breuer, H. Ginsburg, S. Aley, and Z. I. Cabantchik. 1985. Characterization of permeation pathways in the plasma membrane of human erythrocytes infected with early stages of Plasmodium falciparum: association with parasite development. J. Cell Physiol. 125:521-527.
11. Kyes, S., R. Pinches, and C. Newbold. 2000. A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. Mol. Biochem. Parasitol. 105:311-315.
12. McGilvray, I. D., L. Serghides, A. Kapus, O. D. Rotstein, and K. C. Kain. 2000. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 66:3231-3240.
13. Nathoo, S., L. Serghides, and K. C. Kain. 2003. Effect of HIV-1 antiretroviral drugs on cytoadherence and phagocytic clearance of Plasmodium falciparum-parasitised erythrocytes. Lancet 362:1039-1041.
14. Ockenhouse, C. F., M. Ho, N. N. Tandon, G. A. Van Seventer, S. Shaw, N. J. White, G. A. Jamieson, J. D. Chulay, and H. K. Webster. 1991. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J. Infect. Dis. 164:163-169.
15. Patel, N. S., L. Serghides, T. G. Smith, M. Febbraio, R. L. Silvertein, T. W. Kurtz, M. Pravenec, and K. C. Kain. 2004. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J. Infect. Dis. 189:205-213.
16. Pouvelle, B., P. A. Buffet, C. Lepolard, A. Scherf, and J. Gysin. 2000. Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes. Nat. Med. 6:1264-1268.
17. Roberts, D. D., J. A. Sherwood, S. L. Spitalnik, L. J. Panton, R. J. Howard, V. M. Dixit, W. A. Frazier, L. H. Miller, and V. Grinsburg. 1985. Thrombospondin binds falciparum parasitized erythrocytes and may mediate cytoadherence. Nature 318:64-66.
18. Savill, J., L. Dransfield, N. Hogg, and C. Haslett. 1990. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343:170-173.
19. Savill. J., N. Hogg, Y. Ren, and C. Haslett. 1989. Thrombospondin cooperates with CD36 and the Vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Investig. 90:1513-1522.
20. Schwarzer, E., F. Turrini, D. Ulliers, G. Giribaldi, H. Ginsburg, and P. Arese. 1993. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J. Exp. Med. 177:1033-1041.
21. Serghides, L., and K. C. Kain. 2001. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF- secretion by monocytes/macrophages. J. Immunol. 166:6742-6748.
22. Serghides, L., and K. C. Kain. 2002. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet 359:1404-1406.
23. Silamut, K., N. H. Phu, C. Whitty, G. D. Turner, K. Louwrier, N. T. Mai, J. A. Simpson, T. T. Hien, and N. J. White. 1999. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am. J. Pathol. 155:395-410.
24. Smith, T. G., L. Serghides, S. N. Patel, M. Febbraio, R. P. Silverstein, and K. C. Kain. 2003. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. Infect. Immun. 71:393-400.
25. Stevenson, M. M., and E. M. Riley. 2004. Innate immunity to malaria. Nat. Rev. Immunol. 4:169-180.
26. Su, Z., A. Fortin, P. Gros, and M. M. Stevenson. 2002. Opsonin-independent phagocytopsis: an effector mechanism against acute blood-stage Plasmodium chabaudi AS infection. J. Infect. Dis. 186:1321-1329.
27. Tontonoz, P., L. Nagy, J. G. Alvarez, V. A. Thomazy, and R. M. Evans. 1998. PPAR promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252.
28. Treutiger, C. J., A. Heddini, V. Fernandez, W. A. Muller, and M. Wahlgren. 1997. PECAM-1/CD31, an endothelial receptor for binding Plasmodium falciparum-infected erythrocytes. Nat. Med. 3:1405-1408.
29. Udomsangpetch, R., B. Pipitaporn, K. Silamut, R. Pinches, S. Kyes, S. Looareesuwan, C. Newbold, and N. J. White. 2002. Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes. Proc. Natl. Acad. Sci. USA 99:11825-11829.
30. Walliker, D., I. A. Quakyi, T. E. Wellems, T. F. McCutchan, A. Szarfman, W. T. London, L. M. Corcoran, T. R. Burkot, and R. Carter. 1987. Genetic analysis of the human malaria parasite Plasmodium falciparum. Science 236:1661-1666.(Kodjo Ayi, Samir N. Patel)
McLaughlin-Rotman Center for Global Health, McLaughlin Center for Molecular Medicine, University of Toronto
Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada
ABSTRACT
Ring-stage parasitized erythrocytes (RPEs) were demonstrated to interact with effector cells of the innate immune system. With receptor blockade studies and CD36-null macrophages, human and murine macrophages were shown to phagocytose RPEs through the pattern recognition receptor CD36. These in vitro data implicate scavenger receptors in the clearance of RPEs.
TEXT
Phagocytic clearance of Plasmodium falciparum-parasitized erythrocytes (PEs) is an important line of innate defense against malaria (20, 25). Pattern recognition receptors, including CD36, have been implicated in innate clearance of mature-stage PEs (MPEs) by monocytes and macrophages (3, 12, 13, 15, 21, 22, 24, 26). Ring-stage PEs (RPEs) have recently been shown to express ligands capable of interacting with endothelial cells (5, 16, 23, 29). The objective of this study was to examine whether RPEs might also interact with effector cells of the innate immune system.
We demonstrate that murine and human monocyte-derived macrophages can recognize and phagocytose RPEs (see Fig. 1 to 3). To ensure that only ring-stage parasites were used in phagocytosis assays (15, 21), we used procedures (2, 10) to generate highly synchronous ring-stage cultures (purity, >99% RPEs) and used cryopreserved malaria isolates and fresh clinical isolates that only contained RPEs (confirmed by microscopic criteria) (see Fig. 4). To ensure that only RPEs were quantified in phagocytic assays, we used a strict lysis procedure to remove adherent erythrocytes and morphological criteria (12, 23) to ensure that only phagocytosed PE were counted. The slides were read blinded to the experimental conditions and confirmed by a second reader.
To investigate the molecular mechanisms underlying RPE phagocytosis, we undertook receptor blockade studies with monoclonal antibodies (MAbs) against macrophage receptors known to interact with PEs and against macrophage pattern recognition receptors (4, 9) (Fig. 1). Only CD36 receptor blockade resulted in a significant decrease in RPE or MPE phagocytosis. Inhibition of phagocytosis was confirmed with two separate parasite lines: 3D7 (30) and ITG (17).
To confirm the role of CD36 in mediating RPE uptake, we examined phagocytosis by CD36 wild-type and CD36-null macrophages (7, 15). Phagocytosis of RPEs was reduced by 90% in CD36-null macrophages. To investigate whether other macrophage receptors might cooperate with CD36 or mediate uptake in the absence of CD36 (1, 6, 14, 18, 19, 28, 29), we performed phagocytosis assays with wild-type and CD36-null macrophages in the presence of MAbs to other macrophage surface receptors. MAb blockade of receptors other than CD36 did not significantly decrease uptake of RPEs (Fig. 2A). Since pattern recognition receptors such as the mannose receptor have also been implicated in opsonin-independent phagocytosis of P. chabaudi (26), we investigated whether the mannose receptor contributed to RPE uptake. As shown in Fig. 2A, mannan did not significantly decrease uptake of RPEs but did inhibit uptake of MPEs compared to -glucan treatment (data not shown).
Adhesion of MPEs to CD36 is primarily mediated by PfEMP-1. PfEMP-1 is removed from the surface of PEs following mild protease treatment, and cleaving this ligand has been shown to decrease macrophage uptake of MPEs (12, 15, 21). Cytoadhesion of RPEs to endothelial cells has also been reported to be protease sensitive (16). We investigated whether the phagocytosis of RPEs is also dependent upon protease-sensitive ligands on RPEs. Cleavage of surface ligands from RPEs with trypsin reduced the phagocytic clearance of RPEs to the level observed with CD36-null macrophages (Fig. 2B).
The CD36 gene promoter contains a response element recognized by the nuclear receptor heterodimer PPAR-RXR (8, 27), and PPAR-RXR agonists increase CD36 expression and uptake of MPEs (15, 21, 22). We tested the hypothesis that PPAR agonists would increase macrophage uptake of RPEs by upregulating CD36 or other macrophage pattern recognition receptors. Phagocytosis of synchronized RPEs (Fig. 3) or RPEs from cryopreserved or fresh clinical isolates (Fig. 4) was significantly increased by pretreatment of macrophages with PPAR agonists. The increased uptake appeared to be CD36 dependent since it was eliminated by CD36 receptor blockade.
RPE adhesion has been reported in parasites that subsequently acquire the chondroitin sulfate A (CSA)-binding phenotype (16). We examined phagocytosis of RPEs from parasite lines E8B, which binds to CD36, and CS2, which binds to CSA. The uptake of CS2 RPEs was significantly lower than that of E8B RPEs (Fig. 5).
Increasing evidence indicates that innate immune responses contribute to the control of blood-stage malaria infection, lighten the parasite burden, and decrease progression to severe disease (25). In this study, we examined the ability of RPEs to interact with effector cells of the innate immune system. We present evidence that ligands expressed by RPEs confer the capacity for recognition and uptake by macrophages. We demonstrate that human monocyte-derived macrophages and murine macrophages are able to phagocytose RPEs in vitro even in the absence of opsonization and in the presence of an Fc receptor blockade. A role for the scavenger receptor CD36 in mediating nonopsonic phagocytosis of RPEs was supported by the observations that uptake was inhibited by a CD36 blockade, by the cleavage of putative CD36 ligands from the RPEs, and by the elimination of uptake of RPEs by CD36-null macrophages. Furthermore, RPE uptake was significantly increased by cotreatment with the PPAR agonists, which upregulate surface levels of CD36. These data suggest that nonopsonic uptake in vitro appears to be largely dependent on CD36 and not on other macrophage receptors such as ICAM-1, v3, or PECAM-1 or pattern recognition receptors such as the mannose receptor or CD14. These observations are similar to those reported for uptake of MPEs by macrophages (12, 15, 21); however, different surface ligands may interact with CD36 in these cases. For MPEs, previous studies suggest that PfEMP-1 is the primary ligand interacting with CD36 (12, 15, 21). RPEs may express one or more surface ligands capable of interacting with CD36. Pouvelle and colleagues (16) have shown that RPE can adhere to an unknown receptor on syncytiotrophoblast and endothelial cells. Adhesion was dependent upon the presence of a parasite rhoptry-derived ring surface protein, RSP-2 (5). Their studies indicate that RSP-2 appears earlier on malaria-infected erythrocytes than does PfEMP-1, but both ligands may be simultaneously present on the same erythrocyte. In contrast, Udomsangpetch and colleagues attributed RPE cytoadherence to PfEMP-1 (29). The var genes that encode PfEMP-1 have been shown to be expressed as early as 3 h after merozoite invasion (11). Recent data indicate that PfEMP-1 is expressed in RPEs and that trafficking to the membrane is facilitated at elevated temperatures (29). Additional study is required to better characterize the RPE ligand(s) that interacts with CD36.
In summary, our data indicate that the scavenger receptor CD36 participates in clearance of RPEs in vitro and may contribute to innate control of blood-stage infection; however this will require confirmation in vivo.
ACKNOWLEDGMENTS
This work was supported by Canadian Institutes of Health Research (CIHR) operating grant MT-13721 (K.C.K.), a CIHR Canada Research Chair (K.C.K.), and a CIHR fellowship (L.S.).
REFERENCES
1. Berendt, A. R., D. L. Simmons, J. Tansey, C. K. Newbold, and K. Marsh. 1989. Intercellular adhesion molecule 1 (ICAM-1) is an endothelial cytoadherence receptor for Plasmodium falciparum. Nature 341:57-59.
2. Brau-Breton, C., T. L. Rosenberry, and L. H. Pereira da Silva. 1988. Induction of the proteolytic activity of a membrane protein in Plasmodium falciparum by phosphatidyl inositol-specific phospholipase C. Nature 332:457-459.
3. Chuluyan, H. E., and A. C. Issekutz. 1993. VLA-4 can mediate CD11/CD18-independent transendothelial migration of human monocytes. J. Clin. Investig. 92:2768-2777.
4. Deitsch, K. W., and T. E. Wellems. 1996. Membrane modifications in erythrocytes parasitized by Plasmodium falciparum. Mol. Biochem. Parasitol. 76:1-10.
5. Douki, J. B., Y. Sterkers, C. Lepolard, B. Traore, F. T. Coasta, A. Scherf, and J. Gysin. 2003. Adhesion of normal and Plasmodium falciparum ring-infected erythrocytes to endothelial cells and the placenta involves the rhoptry-derived ring surface protein-2. Blood 101:5025-5032.
6. Fadok, V. A., M. L. Warner, D. L. Bratton, and P. M. Henson. 1998. CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (v3). J. Immunol. 161:6250-6257.
7. Febbraio, M., N. A. Abumrad, D. P. Hajjar, K. Sharma, W. Cheng, S. F. A. Pearce, and R. L. Silverstein. 1999. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem. 274:19055-19062.
8. Gearing, K. L., M. Gottlicher, M. Teboul, E. Widmark, and J. A. Gustafsson. 1993. Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc. Natl. Acad. Sci. USA 90:1440-1444.
9. Hoffmann, P. R., A. M. deCathelineau, C. A. Ogden, et al. 2001. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Biol. Chem. 155:649-659.
10. Kutner, S., W. V. Breuer, H. Ginsburg, S. Aley, and Z. I. Cabantchik. 1985. Characterization of permeation pathways in the plasma membrane of human erythrocytes infected with early stages of Plasmodium falciparum: association with parasite development. J. Cell Physiol. 125:521-527.
11. Kyes, S., R. Pinches, and C. Newbold. 2000. A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. Mol. Biochem. Parasitol. 105:311-315.
12. McGilvray, I. D., L. Serghides, A. Kapus, O. D. Rotstein, and K. C. Kain. 2000. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 66:3231-3240.
13. Nathoo, S., L. Serghides, and K. C. Kain. 2003. Effect of HIV-1 antiretroviral drugs on cytoadherence and phagocytic clearance of Plasmodium falciparum-parasitised erythrocytes. Lancet 362:1039-1041.
14. Ockenhouse, C. F., M. Ho, N. N. Tandon, G. A. Van Seventer, S. Shaw, N. J. White, G. A. Jamieson, J. D. Chulay, and H. K. Webster. 1991. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J. Infect. Dis. 164:163-169.
15. Patel, N. S., L. Serghides, T. G. Smith, M. Febbraio, R. L. Silvertein, T. W. Kurtz, M. Pravenec, and K. C. Kain. 2004. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J. Infect. Dis. 189:205-213.
16. Pouvelle, B., P. A. Buffet, C. Lepolard, A. Scherf, and J. Gysin. 2000. Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes. Nat. Med. 6:1264-1268.
17. Roberts, D. D., J. A. Sherwood, S. L. Spitalnik, L. J. Panton, R. J. Howard, V. M. Dixit, W. A. Frazier, L. H. Miller, and V. Grinsburg. 1985. Thrombospondin binds falciparum parasitized erythrocytes and may mediate cytoadherence. Nature 318:64-66.
18. Savill, J., L. Dransfield, N. Hogg, and C. Haslett. 1990. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343:170-173.
19. Savill. J., N. Hogg, Y. Ren, and C. Haslett. 1989. Thrombospondin cooperates with CD36 and the Vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Investig. 90:1513-1522.
20. Schwarzer, E., F. Turrini, D. Ulliers, G. Giribaldi, H. Ginsburg, and P. Arese. 1993. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J. Exp. Med. 177:1033-1041.
21. Serghides, L., and K. C. Kain. 2001. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF- secretion by monocytes/macrophages. J. Immunol. 166:6742-6748.
22. Serghides, L., and K. C. Kain. 2002. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet 359:1404-1406.
23. Silamut, K., N. H. Phu, C. Whitty, G. D. Turner, K. Louwrier, N. T. Mai, J. A. Simpson, T. T. Hien, and N. J. White. 1999. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am. J. Pathol. 155:395-410.
24. Smith, T. G., L. Serghides, S. N. Patel, M. Febbraio, R. P. Silverstein, and K. C. Kain. 2003. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. Infect. Immun. 71:393-400.
25. Stevenson, M. M., and E. M. Riley. 2004. Innate immunity to malaria. Nat. Rev. Immunol. 4:169-180.
26. Su, Z., A. Fortin, P. Gros, and M. M. Stevenson. 2002. Opsonin-independent phagocytopsis: an effector mechanism against acute blood-stage Plasmodium chabaudi AS infection. J. Infect. Dis. 186:1321-1329.
27. Tontonoz, P., L. Nagy, J. G. Alvarez, V. A. Thomazy, and R. M. Evans. 1998. PPAR promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241-252.
28. Treutiger, C. J., A. Heddini, V. Fernandez, W. A. Muller, and M. Wahlgren. 1997. PECAM-1/CD31, an endothelial receptor for binding Plasmodium falciparum-infected erythrocytes. Nat. Med. 3:1405-1408.
29. Udomsangpetch, R., B. Pipitaporn, K. Silamut, R. Pinches, S. Kyes, S. Looareesuwan, C. Newbold, and N. J. White. 2002. Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes. Proc. Natl. Acad. Sci. USA 99:11825-11829.
30. Walliker, D., I. A. Quakyi, T. E. Wellems, T. F. McCutchan, A. Szarfman, W. T. London, L. M. Corcoran, T. R. Burkot, and R. Carter. 1987. Genetic analysis of the human malaria parasite Plasmodium falciparum. Science 236:1661-1666.(Kodjo Ayi, Samir N. Patel)