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RED CELLS
From the Departments of Medicine and Surgery,
University of Toronto, Toronto, Ontario, Canada.
Plasmodium falciparum is the most lethal form of
malaria and is increasing both in incidence and in its resistance to
antimalarial agents. An improved understanding of the mechanisms of
malarial clearance may facilitate the development of new therapeutic
interventions. We postulated that the scavenger receptor CD36, an
important factor in cytoadherence of P
falciparum-parasitized erythrocytes (PEs), might also
play a role in monocyte- and macrophage-mediated malarial clearance. Exposure of nonopsonized PEs to Fc receptor-blocked monocytes resulted in significant PE phagocytosis, accompanied by
intense clustering of CD36 around the PEs. Phagocytosis was blocked
60% to 70% by monocyte pretreatment with monoclonal anti-CD36 antibodies but not by antibodies to Plasmodium falciparum malaria is the
world's most important parasitic disease, responsible for an estimated
300 million to 500 million cases and 1.5 million to 2.7 million deaths
annually.1-3 Deaths occur primarily in young children and
other nonimmune individuals who are at greatest risk for developing
severe and cerebral malaria.1-3 The central
pathophysiologic events in falciparum malaria are the sequestration of
P falciparum-parasitized erythrocytes (PEs) in the
microvasculature of vital organs and the release of proinflammatory cytokines from cells of the monocyte/macrophage (m Phagocytic cells are an essential first line of defense against
malaria. Circulating monocytes and tissue resident m We undertook a study of the molecular mechanisms of P
falciparum phagocytosis based on the hypothesis that monocyte/m Media and reagents
Monocyte and PE preparation
Phagocytosis assay About 2.5 × 105 monocytes were adhered to autoclaved glass coverslips placed in 12-well polystyrene culture plates. For studies of nonopsonic phagocytosis, Fc receptors were first blocked by incubating cells with human IgG Fc fragments (Calbiochem, San Diego, CA) at 20 µg/mL for 25 minutes at room temperature. Following incubation with Fc receptors, monocytes or culture-derived m s were incubated with 10 µg/mL of anti-CD36, CD49d, PECAM-1,
ICAM-1, TSP, or  v 3 antibodies for an
additional 25 minutes and washed with 2 changes of RPMI. PEs were
suspended in 500 µL of RPMI-10% FCS-L-glutamine (L-G) and added to
the monocytes/ms at a PE:cell ratio of 20:1. In experiments to
examine opsonic phagocytosis, PEs were opsonized by exposure to 50%
patient serum (heat-inactivated for 30 minutes at 55°C) for 1 hour at
37°C. Control monocytes/ms were exposed to equivalent numbers of
uninfected erythrocytes (UEs). Plates were rotated gently for 4 hours
at 37°C, 5% CO2. At the end of this time, nonadherent
erythrocytes were washed away with 3 changes of RPMI, and adherent but
nonphagocytosed erythrocytes were lysed in ice-cold distilled water for
30 seconds. Cell preparations were fixed and stained with Giemsa.
Phagocytosis was assessed by light microscopy. From 500 to 1000 monocytes/ms were counted for each coverslip and scored for the
presence or absence of phagocytosed PEs. Criteria for phagocytosis
required the PEs to be contained completely within the monocyte/m
cell outline. The phagocytic index was calculated as the percentage of
monocytes/ms with clear evidence of phagocytosis.
Immunofluorescence After lysis of nonphagocytosed PEs and UEs, monocytes were fixed and permeabilized in ice-cold 100% methanol for 60 seconds. Cells were stained for 1 hour with the monoclonal, fluorescein isothiocynate (FITC)-labeled anti-CD36 OKM5 or with murine monoclonal IC4 antibody specific to antigens expressed on the surface of P falciparum-infected erythrocytes.41 Following 5 washes in phosphate-buffered saline (PBS), Texas red-labeled goat antimouse antibody was added to the IC4 preparations and incubated for an additional hour, after which coverslips were washed in PBS and mounted. In colocalization studies, fixed cell preparations were stained first with IC4/antimouse IgG and then with FITC-labeled OKM5. Microscopy was performed with a Bio-Rad MRC 1024ES confocal microscope and analyzed with Lasersharp software.Surface antigen cross-linking Surface antigens were cross-linked on purified human monocytes using monoclonal antibodies as previously described.42 About 5 × 105 monocytes were suspended in 100-µL RPMI-2% FCS-L-G at 4°C. Fc receptors were blocked by incubating the cells with 20-µg/mL IgG Fc fragments (Calbiochem) at 4°C for 20 minutes followed by washing in RPMI. Surface antigens were then ligated with 10 µg/mL of monoclonal antibody directed against CD36 (OKM5, FA6-152), very late antigen 4 (CD49d, hp2.1), CD18 (7E4), HLA-DR (BL2), or Fc- RIII (3G8). After a 20-minute incubation at 4°C, cells were
washed twice in RPMI, and 5-µg/mL goat antimouse F(ab')2
was added for an additional 20 minutes. After washing in cold RPMI,
cells were resuspended in 500-µL RPMI-2% FCS-L-G and placed in the
37°C, 5% CO2 incubator for times ranging from 5 minutes
to 4 hours.
Assessment of protein, ERK, and p38 MAPK phosphorylation Following antigen cross-linking, monocytes were placed on ice, sedimented, and lysed in ice-cold lysis buffer containing 1% Triton X-100, 150-mmol/L NaCl, 10-mmol/L Tris-HCl (pH 7.4), 2-mmol/L sodium orthovanadate, 100-µg/mL leupeptin, 50-mmol/L NaF, 5-mmol/L EDTA, 1-mmol/L EGTA, and 1-mmol/L phenylmethylsulfonyl fluoride. Postnuclear supernatants were collected after centrifugation at 10 000g for 5 minutes, diluted with 2 × Laemmli buffer, 0.1-mol/L dithiothreitol, and boiled for 4 minutes. Lysates prepared from 100 000 cells were separated on 12.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membrane (Millipore). Blots were then probed with polyclonal rabbit antiphosphotyrosine (Transduction Laboratories, Mississauga, ON, Canada) or antibody specific to the dually phosphorylated, activated forms of the ERK and p38 MAPKs (New England Biolabs, Burlington, ON, Canada). Following incubation with horseradish peroxidase-conjugated secondary antibody (Amersham, Montreal, QC, Canada), blots were developed using an ECL-based system (Amersham).Measurement of monocyte TNF- using a sandwich enzyme-linked immunosorbent assay as described previously.43 Surface CD11b was measured 1 hour after
cross-linking of cell surface antigens or exposure of the cells to
1-µg/mL LPS by flow cytometry. Suspended monocytes were washed in
cold RPMI and resuspended in RPMI-10% FCS-L-G. Phycoerythrin-labeled
anti-CD11b monoclonal antibody (Becton Dickinson) was incubated with
the cells for 20 minutes at 4°C. Cells were washed in cold RPMI and evaluated for staining on a Coulter EPICS XL Cytofluorometer.
Statistical analysis The data are represented as the mean and standard error of the indicated number of experiments. Where representative studies are shown, they are indicative of at least 3 equivalent and independent studies. Statistical comparisons were made for continuous data using one-way ANOVA with post hoc Tukey.
Nonopsonic phagocytosis of P falciparum-infected erythrocytes Monocytes are able to phagocytose P falciparum-infected erythrocytes in the absence of opsonization and in the relatively stringent conditions created by a low PE:monocyte ratio. As shown in Figure 1A (light microscopy) and Figure 1B (immunofluorescence with the PE-specific IC4 monoclonal antibody), the incubation of monocytes with PEs in a complement-free environment results in PE uptake despite Fc receptor blockade of the monocytes and no prior PE opsonization. To avoid quantitating PEs attached to the monocyte but not internalized, we employed both a strict lysis procedure to remove adherent erythrocytes and morphologic criteria to ensure that only phagocytosed PEs were counted. As well, PE phagocytosis was routinely confirmed by confocal microscopy. UEs are not taken up by the monocytes. Monocytes did not have to be adherent for phagocytosis to occur: leukocytes in suspension demonstrated an equivalent ability to ingest PEs (data not shown). In time course studies, we found that nonopsonic PE phagocytosis increased in a linear fashion over the 4-hour course of the assay, with 1 to 4 PEs being ingested by monocytes (data not shown).
Noncomplement-mediated phagocytosis of PEs has been noted previously,
albeit in previously opsonized PEs with a higher PE:monocyte ratio
(200-300:1 vs 20:1).32 A direct comparison of opsonic versus nonopsonic PE phagocytosis was undertaken to determine the
relative efficiencies of both processes over a 4-hour time span. As
seen in Figure 2, opsonic phagocytosis
leads to more PE uptake than the nonopsonic process. Moreover,
opsonized PEs are consumed more avidly, with the typical monocyte
ingesting 4 to 6, as compared with 1 to 4 for nonopsonized PEs. On the
other hand, our results with freshly explanted monocytes likely
underestimate the potential for nonopsonic PE uptake in vivo. Tissue
m
CD36 is clustered during phagocytosis of PEs To begin to investigate the molecular mechanisms underlying nonopsonic PE phagocytosis, monocytes that had ingested PEs were stained with the OKM5 antibody specific to CD36. Cells that have not ingested PEs are outlined by antibodies specific for CD36 but do not show evidence of CD36 clustering (Figure 3A). By contrast, the process of PE uptake by monocytes is accompanied by intense clustering of CD36 in the region of the phagocytosed PEs (Figure 3B). Consistent with a selective role for CD36 in the ingestion of PEs, CD36 clustering is not observed upon ingestion of latex beads coated with Fc fragments (data not shown). Confirmation of the effect is seen in Figure 3C, which demonstrates colocalization of CD36 clustering with ingested PEs as determined by confocal microscopy. As evidenced by these colocalization studies, CD36 clustering was observed in virtually all cells that had ingested PEs. This type of clustering is similar to the clustering of Fc receptors observed during Fc-dependent phagocytosis45 and suggests that CD36 is actively involved in the process of PE phagocytosis.
Nonopsonic phagocytosis of PEs is CD36 dependent but does not use
the
Previous studies examining the phagocytosis of apoptotic cells have
shown that monocyte/m PE adhesion to CD36 is mediated by the variant malarial antigen, P falciparum erythrocyte membrane protein (PfEMP)-1. PfEMP-1 is removed from the surface of the PEs following mild protease treatment.49 We investigated whether the phagocytosis of PEs is dependent upon this CD36 ligand on the infected erythrocyte surface. Proteolytic cleavage of PfEMP-1 from PEs prior to incubation with monocytes reduced their phagocytic clearance to that observed after CD36 receptor blockade with the monoclonal antibodies (Figure 4C). These results suggest that CD36-mediated adhesion is central to the nonopsonic phagocytosis of PEs, although our data do not exclude the possible involvement of other receptors. Induction of tyrosine phosphorylation, ERK, and p38 MAPK phosphorylation by CD36 cross-linking: effect of genistein, PD98059, and SB203580 A cell surface receptor actively involved in phagocytosis would be expected to generate intracellular signaling. We mimicked the intense clustering of CD36 observed during PE phagocytosis by first binding the surface antigen with specific monoclonal antibodies and then adding F(ab')2 fragments directed against the antibody. The method allowed us to study signaling effects specific to CD36 without the confounding effect of other potential PE-monocyte interactions. Cross-linking of CD36 with primary anti-CD36 monoclonals followed by antimouse F(ab')2 fragments results in intense clustering of CD36, similar to that observed with PE phagocytosis, and an increase in intracellular tyrosine phosphorylation (Figure 5A-B), peaking 10 to 20 minutes after cross-linking and then fading (Figure 5B). Importantly, although simple antibody ligation of CD36 did generate a mild increase in tyrosine phosphorylation, cross-linking of the receptor with the addition of F(ab')2 fragments results in considerably more signaling (Figure 5A). The F(ab')2 fragments alone did not stimulate an intracellular signal (Figure 5A); nor did they bind to the monocytes (flow cytometric analysis, data not shown). Together these data are consistent with a signaling role for CD36 clustering.
Antibody-induced clustering of CD36 also leads to accumulation of the dually phosphorylated, active forms of the p42 ERK2, p44 ERK1, and p38 MAPK as judged by Western blot analysis (Figure 5C). Phosphorylation of both the ERK and p38 MAPK proteins peaks within 10 to 20 minutes of CD36 cross-linking but persists through 60 to 120 minutes (Figure 5C). Pretreatment of monocytes with the broad-spectrum tyrosine kinase inhibitor genistein greatly attenuates the accumulation of tyrosine phosphoproteins after CD36 cross-linking, abrogates the induction of phosphorylated ERK, and attenuates the phosphorylation of the p38 MAPK (Figure 5B-C). By contrast, CD36 cross-linking continues to induce phosphorylation of cellular proteins on tyrosine residues after monocyte pretreatment with the MEK-1 selective inhibitor, PD98059, or the p38 MAPK-selective inhibitor, SB203580 (Figure 5D). Consistent with their mechanisms of action, PD98059 abolishes CD36-dependent phosphorylation of the ERK MAPK but has no effect on p38 MAPK phosphorylation, and SB203580, which directly inhibits p38 MAPK activity, does not inhibit either ERK or p38 MAPK phosphorylation (Figure 5E). Taken together, these studies demonstrate that cross-linking of CD36 results in the prolonged phosphorylation of both the ERK and p38 MAPKs. In PE phagocytosis studies, we also observed a similar increase in phosphorylation of the ERK and p38 MAPKs associated with the ingestion of PEs by human monocytes (data not shown). However, because it is difficult to exclude other possible PE-monocyte-induced signaling events associated with these complex cell-cell interactions, these studies are less specific than the antibody cross-linking studies described above. PE phagocytosis is dependent upon the signaling cascades induced by CD36 clustering To determine whether the intracellular signals induced by CD36 cross-linking contribute to the process of PE phagocytosis, monocytes were pretreated with the broad-spectrum tyrosine kinase inhibitor genistein or with selective ERK and p38 pathway inhibitors (PD98059 and SB203580, respectively) or with the Syk kinase-specific inhibitor piceatannol. Genistein, PD98059, and SB203580 diminished phagocytosis by 60%, 40%, and 50%, respectively, and piceatannol had no inhibitory effect (Figure 6). These data suggest that the ERK and p38 MAPK signals are important to nonopsonic PE phagocytosis.
Several lines of evidence suggest that our results are specific and not due to nonspecific pharmacologic effects of PD98059 or SB203580. First, we found no evidence of a nonspecific toxic effect. None of the inhibitors employed exerted monocyte toxicity, as evidenced by more than 96% cell viability (trypan blue exclusion) after 6-hour incubations in their presence. Importantly, the pharmacologic agents did not affect baseline surface CD36 expression over a 6-hour incubation period (flow cytometric data, not shown) and did not affect the number of PEs adhering to the monocyte surface (data not shown). Secondly, both PD98059 and SB203580 may inhibit the cyclooxygenase enzyme.50 However, pretreatment of monocytes with a potent cyclooxygenase inhibitor, indomethacin (100 µmol/L), has no effect on the ingestion of nonopsonized PEs (data not shown). Third, in dose-response experiments we found that 1-, 10-, and 30-µmol/L doses of SB203580 were equally effective at inhibiting nonopsonic PE ingestion (data not shown). Finally, the inhibition of nonopsonized PE uptake by PD203580 and SB203580 is quantifiably different from the effects of these inhibitors on opsonized PE ingestion. In contrast to the 40% inhibition observed with nonopsonic uptake, we found that pretreatment of monocytes with PD98059 (50 µmol/L) inhibited phagocytosis of opsonized PEs by only 9.7% ± 3.5% (mean ± SEM; n = 6). Similarly, SB203580 (1 µmol/L) inhibited nonopsonic ingestion of PEs by 50%, but the same dose had little to no effect on opsonic phagocytosis (inhibition 3.0 ± 3.6%; n = 3). In addition, piceatannol,51 a known inhibitor of Fc-mediated phagocytosis,52 had no inhibitory effect on the phagocytosis of nonopsonized PEs (Figure 6). Thus, the inhibition of nonopsonized PE uptake by PD98059 and SB203580 appears to reflect selective effects of the ERK and p38 MAPK inhibitors and to differ from opsonic phagocytosis. CD36 cross-linking induces increased CD11b expression but not
increased TNF- RIII, results in no or less marked CD11b
up-regulation.
Human monocytes/m
In these studies we describe a novel role for the monocyte/m In this study the majority of nonopsonic P
falciparum-infected erythrocyte phagocytosis is dependent on
surface CD36 and not on other described malarial receptors such as
ICAM-1, TSP, It is unknown why only a small proportion of P
falciparum-infected individuals develop severe or cerebral
malaria. Elevated levels of TNF- Previous studies have described a role for CD36 in the induction of an
early monocyte respiratory burst.53 Although we did find
an early, CD36-dependent increase in surface CD11b (Figure 7), the
significance of this up-regulation is unclear. CD11b functions in part
to promote leukocyte adhesion, but human malaria It has been reported that m We present evidence that protein tyrosine phosphorylation and, specifically, recruitment of the ERK and p38 MAPKs follows CD36 clustering. CD36 has been associated with Src family kinases and recently in the activation of p38 MAPK,36,70,71 providing a possible link between CD36 clustering, increased tyrosine phosphorylation, and accumulation of active ERK and p38 MAPK moieties. Src family kinases have been demonstrated to be upstream of the low molecular weight GTPases involved in activation of MAPK members.72,73 Importantly, we found that clustering of surface CD36 produced far more signaling than simple divalent ligation of the receptor (Figure 5A). This mechanism of signaling is similar to that seen with integrins42,74 and argues strongly that the clustering observed during PE uptake is sufficient to induce intracellular signaling. Pharmacologic inhibition of the intracellular signals induced by CD36 clustering reduces PE phagocytosis, suggesting that CD36 is an active participant in the phagocytic process. The mechanism linking CD36 clustering to PE phagocytosis involves the ERK and p38 MAPKs (Figure 6); further studies are required to elucidate the precise link between CD36 clustering and these pathways. Similarly, it will be of interest to define how the MAPKs contribute to monocyte PE phagocytosis. Recent studies indicate that the ERK and p38 MAPKs may be directly or indirectly associated with cytoskeletal elements such as microtubules and actin and phosphorylate regulatory proteins, providing a possible link between their activation and phagocytosis.75-77 However, the roles of the ERK and p38 MAPKs in phagocytosis are likely to be cell- and stimulus-specific.78-80 The identification of CD36 as a major sequestration receptor has led to
the assumption that it contributes to the pathophysiology of severe
malaria and has prompted the development of antiadherence therapies to
disrupt the CD36-PE interaction.7,16,62,81 However, unlike
ICAM-1, little if any CD36 is expressed on cerebral endothelial cells
or renal glomeruli.6,21,82 CD36 is known to be well
expressed in microvascular endothelial cells from skin, muscle, and
sites rich in resident m
The authors thank Ziyue Lu (Toronto Hospital) for technical assistance and are indebted to Dr M. J. Phillips (Department of Pathology, University of Toronto, Toronto Hospital) for his help with light microscopic analysis, Dr I. Crandall (University of Toronto) for the kind gift of antibody IC4, and Drs. A. Gotlieb and A. Rosenthal (Department of Pathology, University of Toronto, Toronto Hospital) for their kind assistance with confocal microscopy.
Submitted January 20, 2000; accepted June 23, 2000.
Supported by the Medical Research Council of Canada operating grants MT-13721 (K.C.K.) and GR-13298 (O.R.), World Health Organization TDR Programme (TDR 920223; KC.K.), the Heart and Stroke Foundation of Canada (NA-3391; K.C.K.), and a Career Scientist Award from the Ontario Ministry of Health (K.C.K.).
I.D.M. is the recipient of a Medical Research Council of Canada fellowship. L.S. is the recipient of a Medical Research of Canada studentship.
I.D.M. and L.S. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kevin Kain, Tropical Disease Unit, EN G-224, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4; e-mail: kevin.kain{at}uhn.on.ca.
1.
Miller LH, Good MF, Milon G.
Malaria pathogenesis.
Science.
1994;264:1878-1883 2. Kain KC, Keystone JS. Malaria in travelers: epidemiology, disease and prevention. Infect Dis Clin North Am. 1998;12:267-284[Medline] [Order article via Infotrieve]. 3. Anonymous. Malaria, 1982-1997. WHO Weekly Epidemiological Record. 1999;74:265-270[Medline] [Order article via Infotrieve]. 4. MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985;119:385-401[Abstract]. 5. Nagao TH, Uemura T, Yanagi K, Oishi T, Nagatake, Kanbara H. Loss of tumor necrosis factor production by human monocytes in falciparum malaria after their maturation in vitro. Am J Trop Med Hyg. 1996;55:562-566. 6. Turner GD, Morrison H, Jones M, et al. An immunohistochemical study of the pathology of fatal malaria. Am J Pathol. 1994;145:1057-1069[Abstract]. 7. Ockenhouse CF, Ho M, Tandon NN, et al. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J Infect Dis. 1991;164:163-169[Medline] [Order article via Infotrieve]. 8. Berendt AR, Simmons D, Tansey J, Newbold CK, Marsh K. Intercellular adhesion molecule 1 (ICAM-1) is an endothelial cytoadherence receptor for Plasmodium falciparum. Nature. 1989;341:57-59[Medline] [Order article via Infotrieve]. 9. Udomsangpetch R, Reinhardt PH, Schollaardt T, Elliott JF, Kubes P, Ho M. Promiscuity of clinical Plasmodium falciparum isolates for multiple adhesion molecules under flow conditions. J Immunol. 1997;158:4358-4364[Abstract].
10.
Ockenhouse CF, Tegoshi T, Maeno Y, et al.
Human vascular endothelial cell adhesion receptors for Plasmodium falciparum-infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1.
J Exp Med.
1992;176:1183-1189 11. Treutiger CJ, Heddini A, Fernandez V, Muller WA, Wahlgren M. PECAM-1/CD31 and endothelial receptor for binding Plasmodium falciparum-infected erythrocytes. Nat Med. 1997;3:1405-1408[Medline] [Order article via Infotrieve]. 12. Chaiyaroj SC, Angkasekwinai P, Buranakiti A, Looareesuwan S, Rogerson SJ, Brown GV. Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate as a cytoadherence receptor. Am J Trop Med Hyg. 1996;55:76-80. 13. Roberts DD, Sherwood JA, Spitalnik SL, et al. Thrombospondin binds falciparum parasitized erythrocytes and may mediate cytoadherence. Nature. 1985;318:64-66[Medline] [Order article via Infotrieve].
14.
Siano JP, Grady KK, Millet P, Wick TM.
Short report: Plasmodium falciparum: cytoadherence to 15. Oquendo P, Hundt E, Lawler J, Seed B. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell. 1989;58:95-101[Medline] [Order article via Infotrieve]. 16. Ockenhouse CF, Chulay JD. Plasmodium falciparum sequestration: OKM5 antigen (CD36) mediates cytoadherence of parasitized erythrocytes to a myelo-monocytic cell line. J Infect Dis. 1988;157:584-588[Medline] [Order article via Infotrieve].
17.
Ockenhouse CF, Tandon NN, Magowan C, Jamieson GA, Chulay JD.
Identification of a platelet membrane glycoprotein as a falciparum malaria sequestration receptor.
Science.
1989;243:1469-1471
18.
Panton LJ, Leech JH, Miller LH, Howard RJ.
Cytoadherence of Plasmodium falciparum-infected erythrocytes to human melanoma cells lines correlates with surface OKM5 antigen.
Infect Immun.
1987;55:2754-2758 19. Barnwell JW, Ockenhouse CF, Knowles DM. Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum-infected erythrocytes to monocytes, endothelial, and C32 melanoma cells. J Immunol. 1985;135:3494-3497[Abstract]. 20. Newbold C, Warn P, Black G, et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg. 1997;57:389-398. 21. Aikawa M, Iseki M, Barnwell JW, Taylor D, Oo MM, Howard RJ. The pathology of human cerebral malaria. Am J Trop Med Hyg. 1990;43:30-37. 22. Grau GE, Taylor TE, Molyneux ME, et al. Tumour necrosis factor and disease severity in children with falciparum malaria. N Engl J Med. 1989;320:1586-1591[Abstract].
23.
Molyneux ME, Taylor TE, Wirima JJ, Borgstein A.
Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children.
Q J Med.
1989;71:441-459 24. Day NP, Hien TT, Schollaardt T, et al. The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J Infect Dis. 1999;180:1288-1297[Medline] [Order article via Infotrieve]. 25. Brown H, Turner G, Rogerson S, et al. Cytokine expression in the brain in human cerebral malaria. J Infect Dis. 1999;180:1742-1746[Medline] [Order article via Infotrieve].
26.
McGuire W, Hill AVS, Allsopp CEM, Greenwood BM, Kwiatkowski D.
Variation in the TNF- 27. Knight JC, Udalova I, Hill AV, et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999;22:145-150[Medline] [Order article via Infotrieve]. 28. Wahlgren M. Creating deaths from malaria. Nat Genet. 1999;22:120-121[Medline] [Order article via Infotrieve]. 29. Shear HL, Srinivasan R, Nolan T, Ng C. Role of IFN-gamma in lethal and nonlethal malaria in susceptible and resistant murine hosts. J Immunol. 1989;143:2038-2044[Abstract]. 30. Urquhart AD. Putative pathophysiological interactions of cytokines and phagocytic cells in severe human falciparum malaria. Clin Infect Dis. 1994;19:117-131[Medline] [Order article via Infotrieve].
31.
Cappadoro M, Giribaldi G, O'Brien E, et al.
Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency.
Blood.
1998;92:2527-2534
32.
Turrini F, Ginsburg H, Bussolino F, Pescarmona GP, Serra MV, Arese P.
Phagocytosis of Plasmodium falciparum-infected human red blood cells by human monocytes: involvment of immune and non-immune determinants and dependence on parasite developmental stage.
Blood.
1992;80:801-808
33.
Staunton DE, Ockenhouse CF, Springer TA.
Soluble intercellular adhesion molecule 1-immunoglobulin G1 immunoadhesin mediates phagocytosis of malaria-infected erythrocytes.
J Exp Med.
1992;176:1471-1476 34. Ruangjirachuporn W, Afzelius BA, Helmby H, et al. Ultrastructural analysis of fresh Plasmodium falciparum-infected erythrocytes and their cytoadherence to human leukocytes. Am J Trop Med Hyg. 1992;46:511-519. 35. Nogami S, Watanabe J, Nakagaki K, et al. Involvement of macrophage scavenger receptors in protection against murine malaria. Am J Trop Med Hyg. 1998;59:843-845[Abstract]. 36. Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6:41-48[Medline] [Order article via Infotrieve]. 37. Chuluyan HE, Issekutz AC. VLA-4 can mediate CD11/CD18-independent transendothelial migration of human monocytes. J Clin Invest. 1993;92:2768-2777. 38. Robson KJH, Walliker D, Creasey A, McBride J, Beale G, Wilson RJM. Cross-contamination of Plasmodium cultures. Parasitol Today. 1992;8:38-39.
39.
Tragger W, Jensen JB.
Human malaria parasites in continuous culture.
Science.
1976;193:673-675
40.
Serghides L, Crandall I, Hull E, Kain KC.
The Plasmodium falciparum-CD36 interaction is modified by a single amino acid substitution in CD36.
Blood.
1998;92:1814-1819 41. Crandall I, Guthrie N, Sherman IN. Plasmodium falciparum: sera of individuals living in a malaria-endemic region recognize peptide motifs of the human erythrocyte anion transport protein. Am J Trop Med Hyg. 1995;52:450-455.
42.
McGilvray ID, Lu Z, Bitar R, Dackiw APB, Davreux CJ, Rotstein OD.
VLA-4 crosslinking on human monocytic THP-1 cells induces tissue factor expression by a mechanism involving mitogen-activated protein kinase.
J Biol Chem.
1997;272:10287-10294
43.
Brisseau GF, Dackiw APB, Cheung PYC, Christie N, Rotstein OD.
Posttranscriptional regulation of macrophage tissue factor expression by antioxidants.
Blood.
1995;85:1025-1035
44.
Huh HY, Pearce SF, Yesner LM, Schindler JL, Silverstein RL.
Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation.
Blood.
1996;87:2020-2028
45.
Hackam DJ, Rotstein OD, Schreiber A, Zhang WJ, Grinstein S.
Rho is required for the initiation of calcium signaling and phagocytosis by Fc gamma receptors in macrophages.
J Exp Med.
1997;186:955-966
46.
Fadok VA, Warner ML, Bratton DL, Henson PM.
CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor ( 47. Savill J, Dransfield L, Hogg N, Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature. 1990;343:170-173[Medline] [Order article via Infotrieve]. 48. Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest. 1989;90:1513-1522.
49.
Baruch DI, Gormley JA, Ma C, Howard RJ, Pasloske BL.
Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1.
Proc Natl Acad Sci U S A.
1996;93:3497-3502
50.
Borsch-Haubold AG, Pasquet S, Watson SP.
Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase.
J Biol Chem.
1998;273:28766-28772
51.
Oliver JM, Burg DL, Wilson BS, McLaughlin JL, Geahlen RL.
Inhibition of mast cell Fc epsilon R1-mediated signaling and effector function by the Syk-selective inhibitor, piceatannol.
J Biol Chem.
1994;269:29697-29703 52. Matsuda M, Park JG, Wang DC, Hunter S, Chien P, Schreiber AD. Abrogation of the Fc gamma receptor IIA-mediated phagocytic signal by stem-loop Syk antisense oligonucleotides. Mol Biol Cell. 1996;7:1095-1106[Abstract]. 53. Ockenhouse CF, Magowan C, Chulay JD. Activation of monocytes and platelets by monoclonal antibodies or malaria-infected erythrocytes binding to the CD36 surface receptor in vitro. J Clin Invest. 1989;84:468-475. 54. Kwiatkowski D, Cannon JG, Manogue KR, Cerami A, Dinarello CA, Greenwood BM. Tumor necrosis factor production in falciparum malaria and its association with schizont rupture. Clin Exp Immunol. 1989;77:361-366[Medline] [Order article via Infotrieve].
55.
Schofield L, Hackett F.
Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites.
J Exp Med.
1993;177:145-153
56.
Ren Y, Silverstein RL, Allen J, Savill J.
CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis.
J Exp Med.
1995;181:1857-1862
57.
Sambrano GR, Steinberg D.
Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine.
Proc Natl Acad Sci U S A.
1995;92:1396-1400
58.
Sambrano GR, Parthasarathy S, Steinberg D.
Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein.
Proc Natl Acad Sci U S A.
1994;91:3265-3269
59.
Schwartz RS, Olson JA, Raventos-Suarez C, et al.
Altered plasma membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes.
Blood.
1987;69:401-407 60. Facer CA, Agiostratidou G. High levels of anti-phospholipid antibodies in uncomplicated and severe Plasmodium falciparum and in P. vivax malaria. Clin Exp Immunol. 1994;95:304-309[Medline] [Order article via Infotrieve].
61.
Ottnad E, Parthasarathy S, Sambrano GR, et al.
A macrophage receptor for oxidized low density lipoprotein distinct from the receptor for acetyl low density lipoprotein: partial purification and role in recognition of oxidatively damaged cells.
Proc Natl Acad Sci U S A.
1995;92:1391-1395
62.
Baruch DI, Ma XC, Singh HB, Bi X, Pasloske BL, Howard RJ.
Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequence.
Blood.
1997;90:3766-3775 63. Baruch DI, Pasloske BL, Singh HB, et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized erythrocytes. Cell. 1995;82:77-87[Medline] [Order article via Infotrieve].
64.
Picot S, Peyron F, Vuillez J-P, Barbe G, Marsh K, Ambroise-Thomas P.
Tumor necrosis factor production by human macrophages stimulated in vitro by Plasmodium falciparum.
Infect Immun.
1990;58:214-216 65. Debets JMH, Van Der Linden CJ, Dieteren IEM, Leewenberg JFM, Buurman WA. Fc-receptor crosslinking induces rapid secretion of tumor necrosis factor (cachectin) by human peripheral blood monocytes. J Immunol. 1988;141:1197-1201[Abstract].
66.
Debets JMH, Van de Winkel JGJ, Ceuppens JL, Dieteren IEM, Buurman WA.
Cross-linking of both Fc 67. Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med. 1993;177:1033-1041.
68.
Schwarzer E, Alessio M, Ulliers D, Arese P.
Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, CD54, and CD11c in human monocytes.
Infect Immun.
1998;66:1601-1606 69. Leitner WW, Krzych U. Plasmodium falciparum malaria blood stage parasites preferentially inhibit macrophages with high phagocytic activity. Parasite Immunol. 1997;19:103-110[Medline] [Order article via Infotrieve]. 70. Bull HA, Brickell PM, Dowd PM. Src-related protein tyrosine kinases are physically associated with the surface antigen CD36 in human dermal microvascular endothelial cells. FEBS Lett 1994;351:41-44[Medline] [Order article via Infotrieve].
71.
Huang MM, Bolen JB, Barnwell JW, Shattil SJ, Brugge JS.
Membrane glycoprotein IV (CD36) is physically associated with the Fyn, Lyn and Yes protein tyrosine kinases in human platelets.
Proc Natl Acad Sci U S A.
1991;88:7844-7848 72. Stokoe D, McCormick F. Activation of c-Raf-1 by Ras and Src through different mechanisms: activation in vitro and in vivo. EMBO J. 1997;16:2384-2396[Medline] [Order article via Infotrieve]. 73. Erpel T, Courtneidge SA. Src family protein tyrosine kinases and cellular signal transduction pathways. Curr Opin Cell Biol. 1995;7:176-182[Medline] [Order article via Infotrieve].
74.
Miyamoto S, Teramoto H, Coso O, et al.
Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.
J Cell Biol.
1995;131:791-805 75. Morishima-Kawashima M, Kosik KS. The pool of map kinase associated with microtubules is small but constitutively active. Mol Biol Cell. 1996;7:893-905[Abstract]. 76. Earnest S, Khokhlatchev A, Albanesi JP, Barylko B. Phosphorylation of dynamin by ERK2 inhibits the dynamin-microtubule interaction. FEBS Lett. 1996;396:62-66[Medline] [Order article via Infotrieve].
77.
Huang CK, Zhan L, Ai Y, Jongstra J.
LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils.
J Biol Chem.
1997;272:17-19 78. Suchard SJ, Mansfield PJ, Boxer LA, Shayman JA. Mitogen-activated protein kinase activation during IgG-dependent phagocytosis in human neutrophils: inhibition by ceramide. J Immunol. 1997;158:4961-4967[Abstract].
79.
Downey GP, Butler JR, Tapper H, et al.
Importance of MEK in neutrophil microbicidal responsiveness.
J Immunol.
1998;160:434-443 80. McLeish KR, Klein JB, Coxon PY, Head KZ, Ward RA. Bacterial phagocytosis activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades in human neutrophils. J Leukoc Biol. 1998;64:835-844[Abstract]. 81. Cooke BM, Nicoll CL, Baruch DI, Coppel RL. A recombinant peptide based on PfEMP1 blocks and reverses adhesion of malaria-infected red blood cells to CD36 under flow. Mol Microbiol. 1998;30:83-90[Medline] [Order article via Infotrieve].
82.
Silamut K, Phu NH, Whitty C, et al.
A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain.
Am J Pathol.
1999;155:395-410 83. Newbold C, Craig A, Kyes S, Rowe A, Fernandez-Reyes D, Fagan T. Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int J Parasitol. 1999;29:927-937[Medline] [Order article via Infotrieve]. 84. Traore B, Muanza K, Looareesuwan S, et al. Cytoadherence characteristics of Plasmodium falciparum isolates in Thailand using an in vitro human lung endothelial cells model. Am J Trop Med Hyg. 2000;62:38-44[Abstract].
© 2000 by The American Society of Hematology.
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  L. K. Erdman, G. Cosio, A. J. Helmers, D. C. Gowda, S. Grinstein, and K. C. Kain CD36 and TLR Interactions in Inflammation and Phagocytosis: Implications for Malaria J. Immunol., November 15, 2009; 183(10): 6452 - 6459. [Abstract] [Full Text] [PDF]
|
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 R. F. Collins, N. Touret, H. Kuwata, N. N. Tandon, S. Grinstein, and W. S. Trimble Uptake of Oxidized Low Density Lipoprotein by CD36 Occurs by an Actin-dependent Pathway Distinct from Macropinocytosis J. Biol. Chem., October 30, 2009; 284(44): 30288 - 30297. [Abstract] [Full Text] [PDF]
|
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 A. E. Fry, A. Ghansa, K. S. Small, A. Palma, S. Auburn, M. Diakite, A. Green, S. Campino, Y. Y. Teo, T. G. Clark, et al. Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes Hum. Mol. Genet., July 15, 2009; 18(14): 2683 - 2692. [Abstract] [Full Text] [PDF]
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 L. Helming, J. Winter, and S. Gordon The scavenger receptor CD36 plays a role in cytokine-induced macrophage fusion J. Cell Sci., February 15, 2009; 122(4): 453 - 459. [Abstract] [Full Text] [PDF]
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 R. Cholera, N. J. Brittain, M. R. Gillrie, T. M. Lopera-Mesa, S. A. S. Diakite, T. Arie, M. A. Krause, A. Guindo, A. Tubman, H. Fujioka, et al. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin PNAS, January 22, 2008; 105(3): 991 - 996. [Abstract] [Full Text] [PDF]
|
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L. M. Stuart, S. A. Bell, C. R. Stewart, J. M. Silver, J. Richard, J. L. Goss, A. A. Tseng, A. Zhang, J. B. E. Khoury, and K. J. Moore CD36 Signals to the Actin Cytoskeleton and Regulates Microglial Migration via a p130Cas Complex J. Biol. Chem., September 14, 2007; 282(37): 27392 - 27401. [Abstract] [Full Text] [PDF]
|
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 A. A. Lamikanra, D. Brown, A. Potocnik, C. Casals-Pascual, J. Langhorne, and D. J. Roberts Malarial anemia: of mice and men Blood, July 1, 2007; 110(1): 18 - 28. [Abstract] [Full Text] [PDF]
|
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|
S. N. Patel, Z. Lu, K. Ayi, L. Serghides, D. C. Gowda, and K. C. Kain Disruption of CD36 Impairs Cytokine Response to Plasmodium falciparum Glycosylphosphatidylinositol and Confers Susceptibility to Severe and Fatal Malaria In Vivo J. Immunol., March 15, 2007; 178(6): 3954 - 3961. [Abstract] [Full Text] [PDF]
|
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 F. Debierre-Grockiego, L. Schofield, N. Azzouz, J. Schmidt, C. Santos de Macedo, M. A. J. Ferguson, and R. T. Schwarz Fatty Acids from Plasmodium falciparum Down-Regulate the Toxic Activity of Malaria Glycosylphosphatidylinositols. Infect. Immun., October 1, 2006; 74(10): 5487 - 5496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Ockenhouse, W.-c. Hu, K. E. Kester, J. F. Cummings, A. Stewart, D. G. Heppner, A. E. Jedlicka, A. L. Scott, N. D. Wolfe, M. Vahey, et al. Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. Infect. Immun., October 1, 2006; 74(10): 5561 - 5573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Moore and M. W. Freeman Scavenger Receptors in Atherosclerosis: Beyond Lipid Uptake Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1702 - 1711. [Abstract] [Full Text] [PDF]
|
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 V. Aas, M. H. Rokling-Andersen, E. T. Kase, G. H. Thoresen, and A. C. Rustan Eicosapentaenoic acid (20:5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells J. Lipid Res., February 1, 2006; 47(2): 366 - 374. [Abstract] [Full Text] [PDF]
|
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 Q. Chen, P. R. Stone, L. M.E. McCowan, and L. W. Chamley Phagocytosis of Necrotic but Not Apoptotic Trophoblasts Induces Endothelial Cell Activation Hypertension, January 1, 2006; 47(1): 116 - 121. [Abstract] [Full Text] [PDF]
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L. De Franceschi, S. Sada, A. Andreoli, A. Angheben, S. Marocco, and Z. Bisoffi Sickle cell disease and hyperreactive malarial splenomegaly (HMS) in young immigrants from Africa Blood, December 15, 2005; 106(13): 4415 - 4417. [Full Text] [PDF]
|
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S. M. Potter, A. J. Mitchell, W. B. Cowden, L. A. Sanni, M. Dinauer, J. B. de Haan, and N. H. Hunt Phagocyte-Derived Reactive Oxygen Species Do Not Influence the Progression of Murine Blood-Stage Malaria Infections Infect. Immun., August 1, 2005; 73(8): 4941 - 4947. [Abstract] [Full Text] [PDF]
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 L. M. Stuart, J. Deng, J. M. Silver, K. Takahashi, A. A. Tseng, E. J. Hennessy, R. A. B. Ezekowitz, and K. J. Moore Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain J. Cell Biol., August 1, 2005; 170(3): 477 - 485. [Abstract] [Full Text] [PDF]
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I. Gillot, C. Jehl-Pietri, P. Gounon, S. Luquet, M. Rassoulzadegan, P. Grimaldi, and F. Vidal Germ cells and fatty acids induce translocation of CD36 scavenger receptor to the plasma membrane of Sertoli cells J. Cell Sci., July 15, 2005; 118(14): 3027 - 3035. [Abstract] [Full Text] [PDF]
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N. K. Viebig, U. Wulbrand, R. Forster, K. T. Andrews, M. Lanzer, and P. A. Knolle Direct Activation of Human Endothelial Cells by Plasmodium falciparum-Infected Erythrocytes Infect. Immun., June 1, 2005; 73(6): 3271 - 3277. [Abstract] [Full Text] [PDF]
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L. Serghides and K. C. Kain Peroxisome Proliferator-Activated Receptor {gamma} and Retinoid X Receptor Agonists Have Minimal Effects on the Interaction of Endothelial Cells with Plasmodium falciparum- Infected Erythrocytes Infect. Immun., February 1, 2005; 73(2): 1209 - 1213. [Abstract] [Full Text] [PDF]
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K. Ayi, F. Turrini, A. Piga, and P. Arese Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait Blood, November 15, 2004; 104(10): 3364 - 3371. [Abstract] [Full Text] [PDF]
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 K. Asada, S. Sasaki, T. Suda, K. Chida, and H. Nakamura Antiinflammatory Roles of Peroxisome Proliferator-activated Receptor {gamma} in Human Alveolar Macrophages Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 195 - 200. [Abstract] [Full Text] [PDF]
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K. P. O'Dea and G. Pasvol Optimal Tumor Necrosis Factor Induction by Plasmodium falciparum Requires the Highly Localized Release of Parasite Products Infect. Immun., June 1, 2003; 71(6): 3155 - 3164. [Abstract] [Full Text] [PDF]
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B. G. Yipp, S. M. Robbins, M. E. Resek, D. I. Baruch, S. Looareesuwan, and M. Ho Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow Blood, April 1, 2003; 101(7): 2850 - 2857. [Abstract] [Full Text] [PDF]
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 B. C. Urban and D. J. Roberts Inhibition of T Cell Function During Malaria: Implications for Immunology and Vaccinology J. Exp. Med., January 20, 2003; 197(2): 137 - 141. [Full Text] [PDF]
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T. G. Smith, L. Serghides, S. N. Patel, M. Febbraio, R. L. Silverstein, and K. C. Kain CD36-Mediated Nonopsonic Phagocytosis of Erythrocytes Infected with Stage I and IIA Gametocytes of Plasmodium falciparum Infect. Immun., January 1, 2003; 71(1): 393 - 400. [Abstract] [Full Text] [PDF]
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A. Fortin, M.M. Stevenson, and P. Gros Susceptibility to malaria as a complex trait: big pressure from a tiny creature Hum. Mol. Genet., October 1, 2002; 11(20): 2469 - 2478. [Abstract] [Full Text] [PDF]
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K. H. Baek, S. J. Ha, and Y. C. Sung A Novel Function of Phosphorothioate Oligodeoxynucleotides as Chemoattractants for Primary Macrophages J. Immunol., September 1, 2001; 167(5): 2847 - 2854. [Abstract] [Full Text] [PDF]
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L. Serghides and K. C. Kain Peroxisome Proliferator-Activated Receptor {{gamma}}-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis of Plasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-{{alpha}} Secretion by Monocytes/Macrophages J. Immunol., June 1, 2001; 166(11): 6742 - 6748. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
8 per group. 
, P < .001 vs control
UEs; ***, P < .001 vs nonopsonized PEs (ANOVA with post
hoc Tukey).
unlike rodent
malaria