Human Molecular Genetics, 2000, Vol. 9, No. 4 525-530
© 2000 Oxford University Press
A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi)
Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK, 1Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, PO Box 9812, New Haven, CT 06536-0812, USA and 2Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund Laboratories, PO Box123, Lincoln’s Inn Fields, London WC2A 3PX, UK
Received 26 August 1999; Revised and Accepted 10 January 2000.
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ABSTRACT |
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Intercellular adhesion molecule-1 (ICAM-1) is involved in a range of interactions both within the host and between the host and a number of pathogens. Recently we described a mutation within the coding region of the first N-terminal immunoglobulin-like domain of ICAM-1, present at high frequency within African populations, which increased the risk of cerebral malaria. To understand the mechanism by which such a polymorphism might be maintained despite counter-selection by malaria, we have carried out functional assays using both forms of ICAM-1 as soluble Fc chimeric fusion proteins. ICAM-1Kilifi has reduced avidity for LFA-1 compared with ICAM-1ref and binding to soluble fibrinogen was completely abolished with the Kilifi variant. In Plasmodium falciparum adhesion assays, ITO4-A4u binding to ICAM-1Kilifi was reduced compared with binding to the reference form. These results allow for the possibility of balanced selection between the reference and Kilifi forms of ICAM-1 through modulation of inflammatory responses and indicate the existence of differences within ICAM-1-binding P.falciparum isolates which may be relevant to pathogenesis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Plasmodium falciparum-infected erythrocytes are able to bind to a number of endothelial proteins including intercellular adhesion molecule-1 (ICAM-1) (1), CD36 (2), thrombospondin (3), VCAM-1 (4), E-selectin (4), chondroitin sulphate-A (5), P-selectin (6), CD31 (7) and
vß3 (8). The parasite ligand responsible for cytoadherence is thought to be the variant surface antigen [P.falciparum erythrocyte membrane protein 1 (PfEMP1)]. This protein is made up of blocks of amino acids with degenerate homology to the Duffy-binding-like (DBL) regions seen in some Plasmodium invasins (9). It has been suggested that the ability of different parasite lines to bind to varying combinations of endothelial receptors is due to antigenic variation, causing different repertoires of DBLs within the expressed PfEMP1 molecules to be displayed. As well as being a receptor for parasite adhesion, ICAM-1 (CD54) also plays a major role in normal immune function (for a review see ref. 10). It contains five immunoglobulin-like domains which are thought to form a ‘rod-like’ structure on the surface of a range of cell types including leukocytes and endothelium (11–13). The various host functions are mediated by specific interactions with a number of ligands, principally leukocyte function-associated antigen-1 (LFA-1) (10). The plasma protein fibrinogen also binds to ICAM-1 and has a particular role in enhancing CD11b/CD18 (Mac-1)-mediated adhesion (14,15). Through its role in promoting cell–cell contacts and the resulting intercellular signalling, ICAM-1 facilitates leukocyte proliferation and transmigration across activated endothelium.
ICAM-1 also has a role in a diverse spectrum of diseases including pathogen adhesion; for example, P.falciparum-infected erythrocytes (1) and rhinovirus (16–18) and a number of inflammatory disorders such as septic shock (19) and auto-immunity (20). Therefore, modulation of the pathogenesis of these conditions through naturally occurring alleles of ICAM-1 could provide a selective advantage in exposed populations. This is particularly the case for P.falciparum where the respective binding site(s) have been shown only partially to overlap those required for normal host function (21,22).
We have described a coding polymorphism at K29/M in the N-terminal domain of ICAM-1 [ICAM-1Kilifi (23)] which exists in an African population and predisposes towards cerebral malaria, a frequently fatal complication of P.falciparum infection. The discovery of a susceptibility locus at high frequency in a malaria endemic region implies that some other balancing selection is taking place. Given the multiplicity of functions mediated by ICAM-1 we have begun to address why this mutation should be found at high frequency in African populations by comparing the effect of ICAM-1Kilifi with that of ICAM-1ref in a number of functional assays.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Characterization of ICAM-1–Fc recombinant proteins
It was important to demonstrate the overall structural integrity of the chimeric five-domain ICAM-1Kilifi–Fc. Previous work using surface expression on COS cells had demonstrated that most anti-ICAM-1 monoclonal antibodies (mAbs) recognize the Kilifi variant except mAb BBA4 (23). An ELISA was carried out on ICAM-1ref and ICAM-1Kilifi using the same panel of mAbs which demonstrated that the soluble proteins each contained all of the epitopes seen on surface expressed protein (data not shown). In addition, ELISAs were carried out in parallel with the functional studies to ensure that equivalent amounts of protein were immobilized onto the plastic. In these assays a subset of four mAbs showed that the concentration of both forms of the ICAM-1–Fc were equivalent.
The absence of the epitope for mAb BBA4 from ICAM-1Kilifi prompted us to investigate the effect of this mAb on binding of two laboratory lines, ITO4-A4u and ItG-ICAM, compared with mAb 15.2, which is known to block parasitized red blood cell (PRBC) adhesion to ICAM-1. These two lines have been shown to differ in their ability to bind to ICAM-1, being low and high binders, respectively (24). When mAb BBA4 was scored against mAb 15.2 for its inhibition of binding to ICAM-1ref, inhibition of ITO4-A4u binding was approximately twice that of ItG-ICAM with mAb BBA4 (Table 1).
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Differential binding of P.falciparum lines to ICAM-1ref and ICAM-1Kilifi
As the mAb BBA4 varies in its effect on PRBC adhesion (Table 1), we decided to assess binding of the two parasite lines, ItG-ICAM and ITO4-A4u, to the mutated and reference ICAM-1 proteins (24). The result was that equivalent levels of ItG-ICAM bound to ICAM-1ref and ICAM-1Kilifi but for ITO4-A4u the levels of binding on ICAM-1Kilifi were greatly reduced over a range of ICAM-1 concentrations (Fig. 1). These two lines of evidence show that the binding site for ITO4-A4u, in contrast to ItG-ICAM, involves the K29 residue in ICAM-1 domain 1. This is the first evidence that the nature of the interaction between infected erythrocytes and ICAM-1 might differ between different isolates of P.falciparum and that this property may be linked to the pathogenesis of malaria.
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Interaction of LFA-1 with ICAM-1ref and ICAM-1Kilifi
Given the importance of the major leukocyte ß2 integrin, LFA-1, in immune function, we next investigated the ability of this receptor to bind to ICAM-1Kilifi. T cell binding to both forms of ICAM-1 was inhibited by anti-LFA-1 mAb 38 at 10 µg/ml (data not shown). T cells were treated with phorbol ester to stimulate activation of LFA-1 by intracellular signalling and used in a binding assay to immobilized ICAM-1ref and ICAM-1Kilifi. The avidity of ICAM-1Kilifi binding to LFA-1 was less than that of ICAM-1ref, with max values of 3.9 and 1.6 µg/ml, respectively (Fig. 2). However, at protein concentrations that supported maximal T cell binding, 85.5 ± 2.3% of total cells bound to ICAM-1ref and 77.1 ± 2.5% bound to ICAM-1Kilifi. Although this result shows that when saturated binding was achieved both proteins bound similar numbers of T cells, at lower ICAM-1 concentrations LFA-1 on T cells was severely compromised in its ability to bind to ICAM-1Kilifi.
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Loss of fibrinogen binding to ICAM-1Kilifi
Fibrinogen is also an ICAM-1-binding protein with its binding site in domain 1 of ICAM-1 (25,26) and it has a dramatic effect on ICAM-1-mediated adhesion of leukocytes to endothelium (14,15). Therefore, we asked next whether fibrinogen is able to bind to mutated ICAM-1Kilifi. Fibrinogen bound to coated ICAM-1ref in a concentration-dependent manner, reaching a plateau at 50 µg/ml of fibrinogen (Fig. 3) and in agreement with previous observations (25). In contrast, no specific binding of fibrinogen to immobilized ICAM-1Kilifi was detected under the same experimental conditions.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Malaria has played a major role in selecting and maintaining protective polymorphism in endemic regions (27). As the binding of P.falciparum-infected erythrocytes to host endothelium has been associated with fatal complications of this disease (28) and, in particular, binding to ICAM-1 has been implicated in cerebral malaria (29,30), we argued that protective mutations in the N-terminal domain of ICAM-1, which contains the binding site for infected erythrocytes, might occur in malaria-endemic regions. We did identify a polymorphism (K29/M) in the ICAM-1 sequence of East and West Africans (23). Our results showed an association of the K29/M polymorphism with severity of clinical malaria in Kilifi (Kenya), such that individuals homozygous for the M29 allele have increased susceptibility to cerebral malaria. Given the multiplicity of functions that involve ICAM-1 and the diversity of challenges encountered by people in Africa, this is not completely surprising but it does imply that some significant balancing selection is taking place. As well as extending our studies on the binding of P.falciparum to ICAM-1 in this paper, we have concentrated on the role that the K29/M polymorphism in ICAM-1 plays in shaping the immune response through its interactions with LFA-1 and fibrinogen.
The K29/M mutation lies at the end of a loop between ß strands B and C in the crystal structure of the N-terminal domain of human ICAM-1 (12,13). Residues within this loop have been implicated by mutagenesis studies in both LFA-1 and human rhinovirus (HRV) binding (11). Other work has shown that two mAbs mapping to this loop block both fibrinogen and P.falciparum-infected erythrocyte adhesion but have no effect on T cell binding (25). Thus, this loop appears to be involved in a number of interactions.
Binding of the P.falciparum isolate ITO4-A4u to purified ICAM-1Kilifi is reduced at certain protein concentrations relative to ICAM-1ref. Preliminary studies looking at adhesion of PRBCs under flow support the results presented here, indicating that the negative effect of K29/M on ITO4-A4u binding to ICAM-1 is even more pronounced, with virtually no adhesion under physiological flow conditions. This finding may be linked to the dynamic nature of the adhesion of parasitized erythrocytes to ICAM-1 under flow (31).
The infected erythrocyte binding results are particularly interesting with regard to the binding site on ICAM-1. Previous studies identified two different regions, G14–S22 (22) and P36–L43 (21), as being involved in PRBC adhesion. However, these two regions lie very close to each other and it has been assumed that both form part of the binding site. The information from this paper showing differential binding of ItG-ICAM and ITO4-A4u to ICAM-1Kilifi and the varying effect of mAbs 15.2 and BBA4 on PRBC adhesion support the conclusion that different ICAM-1-binding parasites have subtly different binding sites.
How a decrease in parasite binding to ICAM-1Kilifi could be consistent with increased risk of cerebral malaria in ICAM-1Kilifi homozygotes is not clear. One possibility is that the reduced ability of low avidity ICAM-1-binding parasites to adhere to endothelium expressing the ICAM-1Kilifi variant would result in a reduced rate of multiplication and, in competition with high avidity isolates, the latter would be ‘selected’ by the host. If high avidity isolates, such as ItG-ICAM, are more likely to cause severe disease through downstream effects (e.g. more efficient transendothelial signalling), then this would result in a predisposition to severe malarial disease. Further studies are currently being carried out to test this hypothesis.
Another possibility is that the ICAM-1Kilifi allele was originally selected through reduced binding of PRBCs to ICAM-1 and therefore reduced the risk of developing cerebral malaria. During the host–parasite evolution process, compensatory mutations in PfEMP-1 may have been selected for high avidity ICAM-1 binding in areas of high malarial transmission, such as Kenya. With the increase of the population of high avidity ICAM-1-binding parasites, the ICAM-1Kilifi allele has become a cerebral malaria susceptibility allele. However, in areas of low malarial transmission this allele may still be protective. A recent study performed in The Gambia, in an area of low transmission, showed no association of the K/M29 polymorphism with cerebral malaria (32).
We have speculated previously that some other biological selective force must compensate for the increased risk of cerebral malaria seen in individuals carrying the ICAM-1Kilifi gene. Reduced immune responsiveness may have beneficial aspects in a population with a heavy infectious burden, including long-term infections lasting throughout childhood with chronic inflammation. We have examined two prominent features of the immune response which involve the protein ICAM-1. Our previous work showing that the epitopes for two mAbs that block fibrinogen binding to ICAM-1ref were lost in an ICAM-1 construct carrying the mutation D26QPKL/KEDLS indicated that the binding site includes K29 (25). The loss of fibrinogen binding by ICAM-1Kilifi provides direct proof of this finding. Fibrinogen, as a ligand for ICAM-1, plays a number of roles in physiological functions. It has been shown to enhance leukocyte adhesion to endothelium through the integrin Mac-1 (14) and to support transendothelial monocyte migration by acting as a bridging molecule (15). It has been implicated in the mitogenic response of B lymphocytes where it increases cell proliferation (33). Ex vivo experiments using rabbit mesentery showing firm ICAM-1/fibrinogen-dependent adhesion of monocytes to endothelium have also suggested a role in leukocyte recirculation. Additionally, binding of fibrinogen to ICAM-1 on saphenous rings modulates vascular tone, via a non-nitric oxide-dependent pathway, supporting the ability of ICAM-1 to promote signal transduction. The effect of the Kilifi mutation on LFA-1 binding, as measured by adhesion of activated T cells, is more complex. At lower coating concentrations of ICAM-1 there is a major difference in T cell adhesion that is not seen at higher coating concentrations. This finding suggests that differences between the two variants at relatively low levels of protein may affect vascular surveillance mechanisms such that ICAM-1Kilifi homozygotes would have a higher threshold for triggering an inflammatory response. Thus, the loss of fibrinogen binding and reduced LFA-1-mediated adhesion of leukocytes in ICAM-1Kilifi homozygotes could result in a beneficial immunomodulatory effect; for example, decreased ICAM-1-dependent leukocyte-mediated tissue damage due to chronic exposure to infectious agents.
As HRV binding could reasonably have a significant impact on childhood mortality in Africa through secondary bacterial infection, we are currently investigating the effect of ICAM-1Kilifi on HRV adhesion. In one study a K29/E replacement had no significant effect on HRV adhesion (34), whereas in another study a K29/L mutation resulted in the loss of HRV15 binding but not that of five other HRV serotypes (35). The latter result suggests that, as for P.falciparum-infected erythrocytes, different HRV serotypes may have variable, but overlapping, binding sites on human ICAM-1. The analysis of this interaction and its impact on productive viral invasion and disease will require detailed studies at both cellular and epidemiological levels.
In conclusion, through our observations on parasite and LFA-1/fibrinogen adhesion, we have begun to address the role of the ICAM-1Kilifi mutation in African populations both in increasing the risk of cerebral malaria and in providing a counter-selection to this increased risk. Further studies will be required to elucidate the complex interplay between this multifunctional protein in the host, including the balance between protective and destructive immunity in different geographical contexts, the possibility of balancing polymorphisms in ICAM-1 ligands and the broad selective pressures encountered by African children in deter- mining susceptibility and resistance to infectious agents.
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MATERIALS AND METHODS |
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Materials
All chemicals were from Sigma (Dorset, UK) unless otherwise indicated.
Recombinant protein production
A five-domain ICAM-1Kilifi–Fc was constructed based on our existing ICAM-1ref–Fc constructs (24). Direct mutagenesis of the five-domain form was not possible due to the presence of common restriction sites for cloning in the vector and insert. Therefore a three-domain version containing the K29/M mutation was made by PCR mutagenesis (36) of our existing three-domain reference form. The region containing the mutation was then transferred to a five-domain ICAM-1–Fc backbone on a BssSI fragment. Constructs were checked by DNA sequencing (data not shown). ICAM-1–Fc (both reference and Kilifi variants) were expressed as dimerized chimeric molecules consisting of the five extracellular domains of ICAM-1 linked at the C-terminus to the hinge region and third and fourth domain of the human IgG1 heavy chain, the Kilifi variant differing from the reference form by a single substitution of a methionine for a lysine residue at position 29. The recombinant proteins were expressed and purified as previously described (21).
For all adhesion assays the relative amounts of the ICAM-1 proteins were assayed simultaneously by ELISA using a panel of mAbs, including mAb BBA4 which is sensitive to the K29/M mutation (23), to ensure that both reference and Kilifi ICAM-1 proteins were folded correctly and used in assays at comparable concentrations. For this ELISA, recombinant ICAM-1 protein was adsorbed directly onto the wells of a 96-well ELISA plate (Immunosorb; Nunc/Gibco, Paisley, UK) in a dilution series and incubated for 2 h at 37°C. The plates were blocked with phosphate-buffered saline (PBS)/1% bovine serum albumin (BSA) overnight at 4°C. The blocking solution was removed and the plates incubated with the mAbs at 5 µg/ml on ice for 1 h. The mAbs were removed and the wells washed thoroughly three times with PBS/1% BSA. Affinity-purified anti-mouse Fc-peroxidase-conjugated antibody (Sigma) was added to each well and incubated again for 1 h at 4°C. The plates were washed with PBS/1% BSA four times and peroxidase activity was detected using o-phenylenediamine.
Plasmodium falciparum adhesion assay
ITO4-A4u and ItG-ICAM are parasite lines able to bind to human ICAM-1. ITO4-A4u is derived from ITO4-A4, a clone originating from the Brazilian IT4/25/5 line (1), by selection on a variant-specific mAb BC6 (37), whereas ItG-ICAM was generated by repeated selection on ICAM-1 and was a gift from Dr C. Ockenhouse (Walter Reed Army Institute of Research, Washington, DC). Parasites were cultured in human group O erythrocytes as previously described (38,39).
Proteins were adsorbed onto 60 x 15 mm bacteriological Petri dishes (Falcon 1007; Becton Dickinson, Oxford, UK) at varying concentrations in a radial pattern using 2 µl spots as previously described (29). The dishes were placed in a wet-box at 37°C for 1–2 h to allow the proteins to adsorb to the surface, after which the protein solutions were removed by aspiration and the plates blocked by treatment with PBS/1% BSA overnight at 4°C. The blocking solution was removed and the plates washed twice in binding medium (RPMI 1640 medium without bicarbonate, 10 mM glucose, 25 mM HEPES; 1% BSA) prior to adding 1.25 ml of parasite suspension at ~2% haematocrit/2–7% parasitaemia. The plates were incubated at 37°C for 60 min with gentle resuspensions every 10 min. Unbound erythrocytes were removed by 4–6 washes with 1.5 ml of binding medium followed by a final wash with protein-free binding medium with monitoring via the use of an inverted microscope. The dishes were fixed in protein-free binding medium/1% glutaraldehyde for 40 min and stained with 5% Giemsa for 20 min. Parasite adhesion was scored by microscopy counting five high-power fields (x400) (~0.3 mm2).
T cell adhesion assay
Immulon 1 96-well plates (Dynatech, Middlesex, UK) were coated overnight at 4°C with 0–40 µg/ml ICAM-1ref or ICAM-1Kilifi. Non-specific sites were then blocked with 2.5% BSA in PBS for 1 h at room temperature and unbound protein removed by four washes with RPMI-1640. T cells, cultured as previously described (40), were washed and resuspended at 4 x 106/ml in HEPES buffer (20 mM HEPES, 140 mM NaCl, 2 mg/ml glucose, pH 7.4) and labelled with 2.5 µM BCECF/AM (Calbiochem, San Diego, CA) for 30 min at 37°C. The cells were then washed and resuspended at 2 x 106/ml in RPM1-1640 containing 50 nM phorbol-12,13-dibutyrate and 100 µl of these cells added to each well of the ICAM-1–Fc-coated plates. The plates were spun for 1 min at 30 g and incubated for 30 min at 37°C, then unbound cells removed by two to four washes with prewarmed HEPES buffer containing 0.4 mM MgCl2 and 0.4 mM CaCl2. The bound cells were quantified using a fluorescence plate reader (Fluoroskan II; Labsystems, Cambridge, UK).
Fibrinogen adhesion assay
Five-domain ICAM-1Kilifi, ICAM-1ref or transferrin (control) were immobilized at 5 µg/ml onto Immulon 96-well plates (Dynex Technologies, Chantilly, VA) for 18 h at 4°C. The proteins were then aspirated and the plate blocked by treatment with Tris-buffered saline (pH 8.0) containing 1% BSA for 2 h at 37°C. The blocking solution was removed and the plate washed twice with Tris buffer. Increasing concentrations (0–100 µg/ml) of fibrinogen purified from human plasma (41) in Tris containing 0.1% BSA, 0.1% Tween and 2.5 mM Ca2+ were then added for 40 min at 22°C. At the end of incubation, unbound fibrinogen was aspirated and the plate was washed twice with Tris buffer and incubated with a polyclonal rabbit anti-fibrinogen antibody (Calbiochem) at 1:2000 dilution in Tris buffer for 1 h at 37°C. After two washes, the plate was incubated with biotinylated goat anti-rabbit IgG for an additional 1 h incubation at 37°C, washed and incubated with alkaline phosphatase-conjugated streptavidin for 45 min at 22°C. Detection of bound antibody under the various conditions tested was carried out by addition of p-nitrophenyl phosphate substrate and determination of optical density at 
= 405 nm.
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ACKNOWLEDGEMENTS |
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We thank Dr Andrew Gearing (British Biotechnology, Oxford) for the gift of mAb BBA4, Dr Chris Ockenhouse (WRAIR, Washington, DC) for providing the parasite line ItG-ICAM, Robert Pinches for technical assistance, Dr Sue Kyes for DNA sequencing and Dr Sue Adams for measurements of PRBC adhesion under flow. We are also grateful to Dr Anthony Berendt for his support and enthusiasm for the project. This work was supported by the Wellcome Trust, CONICIT (D.F.-R.), the Imperial Cancer Research Fund, NIH grant RO1-HL43773 and an American Heart Association Established Investigator Award (D.C.A.).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 151 708 9393; Fax: +44 151 708 9007; Email: agcraig@liverpool.ac.uk
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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