Parasite ligand–host receptor interactions during invasion of erythrocytes by Plasmodium merozoites

doi:10.1016/j.ijpara.2004.10.010

International Journal for Parasitology

Volume 34, Issues 13–14, December 2004, Pages 1413-1429

https://doi.org/10.1016/j.ijpara.2004.10.010 Get rights and content

Abstract

Malaria parasites must recognise and invade different cells during their life cycle. The efficiency with which Plasmodium falciparum invades erythrocytes of all ages is an important virulence factor, since the ability of the parasite to reach high levels of parasitemia is often associated with severe pathology and morbidity. The merozoite invasion of erythrocytes is a highly complex, multi-step process that is dependent on a cascade of specific molecular interactions. Although many proteins are known to play an important role in invasion, their functional characteristics remain unclear. Therefore, a complete understanding of the molecular interactions that are the basis of the invasion process is absolutely crucial, not only in improving our knowledge about the basic biology of the malarial parasite, but also for the development of intervention strategies to counter the disease. Here we review the current state of knowledge about the receptor–ligand interactions that mediate merozoite invasion of erythrocytes.

Introduction

Malaria is a major human disease that accounts for almost 2 million deaths annually. The malaria parasites have a complex life cycle involving both a vertebrate and an invertebrate host. Survival and transmission depends on the ability of the invasive stages of the parasite to recognise and invade the appropriate host cell types. The asexual erythrocytic phase of the Plasmodium life cycle is responsible for producing the clinical features and pathology associated with malaria. To begin the erythrocytic phase, the exoerythrocytic schizonts in the liver release merozoites that invade erythrocytes and develop there through the ring, trophozoite and schizont stages. Numerous molecules that are implicated in the invasion process have been identified in apical organelles (rhoptry, micronemes) and on both the merozoite and erythrocyte surfaces (Table 1). The functions of only a few of these molecules are well characterised and the molecular mechanisms involved at each step of invasion are not well understood.

Section snippets

The steps in the invasion process

The invasion of erythrocytes by Plasmodium merozoites is a complex, multistep process and the sequence of invasive steps is probably similar for all Plasmodium species. The description of invasion is based on videomicroscopy (Dvorak et al., 1975) and ultrastructural analysis (Aikawa et al., 1978, Miller et al., 1979, Aikawa et al., 1981, Aikawa and Miller, 1983, Bannister and Dluzewski, 1990, Bannister et al., 2000). In the first step, the merozoite attaches reversibly to the erythrocyte

Duffy blood group antigen as receptor in erythrocyte invasion

The human malaria parasite, P. vivax and the related simian parasite P. knowlesi invade human erythrocytes using the Duffy blood group antigen as the receptor (Miller et al., 1975, Miller et al., 1976, Barnwell et al., 1989). The Duffy blood group antigen is a chemokine receptor (Chaudhuri et al., 1993, Horuk et al., 1993) that binds a family of chemokines including IL-8 and MGSA, melanoma growth stimulatory activity (Horuk et al., 1993, Hesselgesser et al., 1995). The evidence that junction

DBL family

The P. vivax/P. knowlesi Duffy-Binding Protein (DBP) that binds to the Duffy blood group antigen on the erythrocyte surface is characterised by the presence of a cysteine-rich region near the N-terminus, a low complexity intermediate region, followed by another cysteine-rich region, a transmembrane and a short cytoplasmic tail. Although P. falciparum invades Duffy-negative erythrocytes and is not dependent on the Duffy blood group antigen for erythrocyte invasion, a family of erythrocyte

Reticulocyte binding like (RBL) protein family

Plasmodium vivax is known to invade only reticulocytes and not mature erythrocytes. Since reticulocytes comprise a minority (∼1%) of the total erythrocyte population, P. vivax merozoites would interact with numerous mature erythrocytes in circulation before encountering a reticulocyte. Junction formation irreversibly commits the parasite to invade the erythrocyte and involves the Duffy blood group antigen expressed on all circulating erythrocytes. Barnwell and coworkers suggested that a

Redundancy in invasion of Plasmodium falciparum

Numerous studies have indicated that malarial merozoites, especially from P. falciparum and P. knowlesi, have the ability to invade erythrocytes through several invasion pathways. Evidence for alternative invasion pathways was provided by P. falciparum strains that invaded glycophorin A-deficient erythrocytes (Miller et al., 1977, Pasvol et al., 1982a) and sialic acid-deficient erythrocytes (Mitchell et al., 1986). These studies using different enzymatically treated target erythrocytes showed

Erythrocyte receptor polymorphism

The glycophorins represent examples of erythrocyte receptor polymorphism that appears to influence susceptibility to malaria. As mentioned previously different glycophorin molecules (A, B, C/D) play important roles as erythrocyte receptors in the invasion process. However, none of the erythrocytes containing different polymorphic forms of the glycophorins emulate the Duffy system. All glycophorin polymorphisms decrease invasion partially, but do not block it completely. For example, invasion

Challenges for the future

The steps of erythrocyte invasion by Plasmodium merozoites have been defined by videomicroscopy and ultrastructural analysis. However, these studies cannot define the biochemical events that allow invasion to proceed. Some of the questions about erythrocyte invasion that are unanswered and remain to be explored are as follows: (i) The protease that prepares the P. chabaudi erythrocytes for invasion (Breton et al., 1992) and the step that it involves remain undefined. Is there a similar protease

Acknowledgements

We wish to thank Dr John Adams for sharing his unpublished data.

References (152)

J.H. Adams et al.
The Duffy receptor family of i is located within the micronemes of invasive malaria merozoites
Cell
(1990)
J.H. Adams et al.
An expanding ebl family of Plasmodium falciparum
Trends Parasitol.
(2001)
L.H. Bannister et al.
A brief illustrated guide to the ultrastructure of Plasmodium falciparum asexual blood stages
Parasitol. Today
(2000)
C.G. Black et al.
Merozoite surface protein 8 of Plasmodium falciparum contains two epidermal growth factor-like domains
Mol. Biochem. Parasitol.
(2001)
C.G. Black et al.
Apical location of a novel EGF-like domain-containing protein of Plasmodium falciparum
Mol. Biochem. Parasitol.
(2003)
M.J. Blackman et al.
Processing of the Plasmodium falciparum major merozoite surface protein-1: identification of a 33-kilodalton secondary processing product which is shed prior to erythrocyte invasion
Mol. Biochem. Parasitol.
(1991)
M.J. Blackman et al.
Plasmodium knowlesi: secondary processing of the malaria merozoite surface protein-1
Exp. Parasitol.
(1996)
Y. Colin
Gerbich blood groups and minor glycophorins of human erythrocytes
Transfus. Clin. Biol.
(1995)
P.H. David et al.
Processing of a major parasite surface glycoprotein during the ultimate stages of differentiation in Plasmodium knowlesi
Mol. Biochem. Parasitol.
(1984)
J.A. Deans et al.
Biosynthesis of a putative protective Plasmodium knowlesi merozoite antigen
Mol. Biochem. Parasitol.
(1984)

S.A. Dolan et al.

Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes

Mol. Biochem. Parasitol.

(1994)

T.S. Fraser et al.

Erythrocyte-binding activity of Plasmodium yoelii apical membrane antigen-1 expressed on the surface of transfected COS-7 cells

Mol. Biochem. Parasitol.

(2001)

M.R. Galinski et al.

A reticulocyte-binding protein complex of Plasmodium vivax merozoites

Cell

(1992)

P. Gerold et al.

Structural analysis of the glycosyl–phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum

Mol. Biochem. Parasitol.

(1996)

T.W. Gilberger et al.

A novel EBA-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes

J. Biol. Chem.

(2003)

J. Hesselgesser et al.

A mutant of melanoma growth stimulating activity does not activate neutrophils but blocks erythrocyte invasion by malaria

J. Biol. Chem.

(1995)

A.N. Hodder et al.

The disulfide bond structure of Plasmodium apical membrane antigen-1

J. Biol. Chem.

(1996)

S.A. Howell et al.

Proteolytic processing and primary structure of Plasmodium falciparum apical membrane antigen-1

J. Biol. Chem.

(2001)

S.A. Howell et al.

A single malaria merozoite serine protease mediates shedding of multiple surface proteins by juxtamembrane cleavage

J. Biol. Chem.

(2003)

O. Kaneko et al.

Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone of Plasmodium falciparum does not affect erythrocyte invasion

Mol. Biochem. Parasitol.

(2000)

O. Kaneko et al.

Gene structure and expression of a Plasmodium falciparum 220-kDa protein homologous to the Plasmodium vivax reticulocyte binding proteins

Mol. Biochem. Parasitol.

(2002)

J. Keen et al.

Identification of the gene for a Plasmodium yoelii rhoptry protein. Multiple copies in the parasite genome

Mol. Biochem. Parasitol.

(1990)

J.K. Keen et al.

A gene coding for a high-molecular mass rhoptry protein of Plasmodium yoelii

Mol. Biochem. Parasitol.

(1994)

A. Kushwaha et al.

Expression and characterisation of Plasmodium falciparum acidic basic repeat antigen expressed in Escherichia coli

Mol. Biochem. Parasitol.

(2000)

A. Kushwaha et al.

Amino terminus of Plasmodium falciparum acidic basic repeat antigen interacts with the erythrocyte membrane through band 3 protein

Mol. Biochem. Parasitol.

(2002)

X. Li et al.

A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3

J. Biol. Chem.

(2004)

H. Liang et al.

Conservation of structure and function of the erythrocyte-binding domain of Plasmodium falciparum EBA-175

Mol. Biochem. Parasitol.

(1997)

C.A. Lobo et al.

Glycophorin C is the receptor for the Plasmodium falciparum erythrocyte binding ligand PfEBP-2 (baebl)

Blood

(2003)

S. Longacre

The Plasmodium cynomolgi merozoite surface protein 1 C-terminal sequence and its homologies with other Plasmodium species

Mol. Biochem. Parasitol.

(1995)

S. Longacre et al.

Plasmodium vivax merozoite surface protein 1 C-terminal recombinant proteins in baculovirus

Mol. Biochem. Parasitol.

(1994)

V.M. Marshall et al.

Close linkage of three merozoite surface protein genes on chromosome 2 of Plasmodium falciparum

Mol. Biochem. Parasitol.

(1998)

J.S. McBride et al.

Fragments of the polymorphic Mr 185,000 glycoprotein from the surface of isolated Plasmodium falciparum merozoites form an antigenic complex

Mol. Biochem. Parasitol.

(1987)

D.J. McColl et al.

Conservation of structural motifs and antigenic diversity in the Plasmodium falciparum merozoite surface protein-3 (MSP-3)

Mol. Biochem. Parasitol.

(1997)

J.H. Adams et al.

A family of erythrocyte binding proteins of malaria parasites

Proc. Natl Acad. Sci. USA

(1992)

M. Aikawa et al.

Structural alteration of the erythrocyte membrane during malarial parasite invasion and intraerythrocytic development

Ciba Found. Symp.

(1983)

M. Aikawa et al.

Erythrocyte entry by malarial parasites. A moving junction between erythrocyte and parasite

J. Cell Biol.

(1978)

M. Aikawa et al.

Freeze-fracture study on the erythrocyte membrane during malarial parasite invasion

J. Cell Biol.

(1981)

S.J. Allen et al.

Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3

Am. J. Trop. Med. Hyg.

(1999)

L.H. Bannister et al.

The ultrastructure of red cell invasion in malaria infections: a review

Blood Cells

(1990)

L.H. Bannister et al.

Plasmodium falciparum apical membrane antigen 1 (PfAMA-1) is translocated within micronemes along subpellicular microtubules during merozoite development

J. Cell Sci.

(2003)

J.W. Barnwell et al.

Invasion of erythrocytes

J.W. Barnwell et al.

In vitro evaluation of the role of the Duffy blood group in erythrocyte invasion by Plasmodium vivax

J. Exp. Med.

(1989)

J. Baum et al.

Erythrocyte invasion phenotypes of Plasmodium falciparum in the Gambia

Infect. Immun.

(2003)

J. Baum et al.

Evidence for diversifying selection on erythrocyte-binding antigens of Plasmodium falciparum and P. vivax

Genetics

(2003)

M.J. Blackman et al.

A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies

J. Exp. Med.

(1990)

M.J. Blackman et al.

Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein

J. Exp. Med.

(1994)

P.L. Blair et al.

Transcripts of developmentally regulated Plasmodium falciparum genes quantified by real-time RT-PCR

Nucleic Acids Res.

(2002)

P.B. Booth et al.

Gerbich blood group system: a useful genetic marker in certain Melanesians of Papua and New Guinea

Nature

(1970)

M.F. Boyd et al.

Studies on benign tertian malaria. IV. On the refractariness of negroes to inoculation with Plasmodium vivax

Am. J. Hyg.

(1933)

C.B. Breton et al.

Plasmodium chabaudi p68 serine protease activity required for merozoite entry into mouse erythrocytes

Proc. Natl Acad. Sci. USA

(1992)

Cited by (184)

A C2 domain containing plasma membrane protein of Plasmodium falciparum merozoites mediates calcium-dependent binding and invasion to host erythrocytes
2023, Journal of Microbiology, Immunology and Infection
Invasion of red blood cells by Plasmodium falciparum merozoites is governed by multiple receptor–ligand interactions which are critical for bridging the two cells together. The critical function of these ligands for invasion and their direct exposure to the host immune system makes them lucrative vaccine candidates. This necessitates the discovery of new adhesins with less redundancy that mediates the binding of merozoite to the red cell, and furthermore invasion into it. Here we have identified a novel membrane associated antigen (PfC2DMA) that is conserved throughout the Plasmodium species and has a membrane targeting C2 domain at its extreme N-terminal region.
Recombinant C2_dom was expressed heterologously in bacteria and purified to homogeneity. Mice antisera against C2_dom was raised and used to check the expression and intraparasitic localization of the protein. RBC and Ca²⁺ ion binding activity of C2_dom was also checked.
C2_dom exhibited specific binding to Ca²⁺ ions and not to Mg²⁺ ions. PfC2DMA localized to the surface of merozoite and recombinant C2_dom bound to the surface of human RBCs. RBC receptor modification by treatment with different enzymes showed that binding of C2_dom to RBC surface is neuraminidase sensitive. Mice antisera raised against C2_dom of Pf C2DMA showed invasion inhibitory effects.
Our findings suggest that C2_dom of PfC2DMA binds to surface of red cell in a Ca²⁺-dependent manner, advocating a plausible role in invasion and can serve as a potential novel blood stage vaccine candidate.
A novel platform for peptide-mediated affinity capture and LC-MS/MS identification of host receptors involved in Plasmodium invasion
2021, Journal of Proteomics
Successful Plasmodium falciparum invasion of red blood cells includes the orderly execution of highly specific receptor-ligand molecular interactions between the parasite's proteins and the red blood cell membrane proteins. There is a growing need for elucidating receptor-ligand pairings, which will help in understanding the parasite's biology and provide the fundamental basis for developing prophylactic or therapeutic alternatives leading to mitigating or eliminating this type of malaria.
We have thus used Plasmodium falciparum RH5 - derived peptides and ghost red blood cell proteins in synthetic peptide affinity capture assays to identify important host receptors used by Plasmodium spp. in the invasion of red blood cells. LC-MS/MS analysis confirmed the extensively described interaction between PfRH5 and the basigin receptor on the red blood cell membrane.
As shown here, tagged synthetic peptides displaying high binding ability to erythrocytes can be used to identify receptors present in protein extracts from ghost red blood cells via affinity capture and LC-MS/MS.
The article describes a novel approach for identifying red blood cell receptors based on the ability of synthetic peptides having high red blood cell binding capacity to capture Plasmodium spp. receptors on proteins extracted from ghost red blood cells. Specifically, novel methods to identify Plasmodium falciparum reticulocyte binding protein homolog 5 PfRH5 and basigin interaction using a combination of affinity capture and LC-MS/MS assays is described. Identification of these host RBC receptors interacting with malarial parasite proteins is of utmost importance in studying the disease's pathogenesis and will provide crucial information in understanding the parasite's biology. In addition, data from these studies can be used to identify potential therapeutic target(s) to mitigate or eliminate this debilitating disease.
CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development
2021, Computational and Structural Biotechnology Journal
Calcium ions are used as important signals during various physiological processes. In malaria parasites, Plasmodium spp., calcium dependent protein kinases (CDPKs) have acquired the unique ability to sense and transduce calcium signals at various critical steps during the lifecycle, either through phosphorylation of downstream substrates or mediating formation of high molecular weight protein complexes. Calcium signaling cascades establish important crosstalk events with signaling pathways mediated by other secondary messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). CDPKs play critical roles at various important physiological steps during parasite development in vertebrates and mosquitoes. They are also important for transmission of the parasite between the two hosts. Combined with the fact that CDPKs are not present in humans, they continue to be pursued as important targets for development of anti-malarial drugs.
Polymorphism and natural selection in the merozoite surface protein 3F2 (PVX_97710) locus of Plasmodium vivax among field isolates
2020, Infection, Genetics and Evolution
Plasmodium vivax, the chronic relapsing human malaria parasite with the most widespread distribution, possesses proteins associated with the merozoite surface that could be targets for host immune responses and potential vaccine candidates. Of these, the merozoite surface protein 3 of P. vivax (PvMSP3) is an attractive vaccine target as well as a genetic marker for epidemiological surveillance. PvMSP3 comprises a group of protein members encoded by a multigene family. Although some protein members, i.e. PvMSP3α and PvMSP3β, have been targets for molecular and immunological investigations, the most abundantly expressed protein member during late asexual erythrocytic stages, PvMSP3F2 (PVX_97710), remains unexplored.
To address domain organization and evolution of this locus, the complete coding sequences of 31 P. vivax isolates from diverse malaria endemic areas of Thailand were analyzed and compared with 10 previously reported sequences. Results revealed that all PvMSP3F2 sequences differed but could be divided into 5 repeat-containing domains flanked by 6 non-repeat domains. Repeat domains II and IV at the 5′ portion and domain X at the 3′ portion exhibited extensive sequence and length variation whereas repeat domains VI and VIII located at the central region were relatively conserved. Despite a repertoire of PvMSP3F2 variants, predicted coiled-coil tertiary structure and predicted B-cell epitopes seem to be maintained. Evidence of intragenic recombination has been detected among field isolates in Thailand that could enhance sequence diversity at this locus. Non-repeat domains I and IX located at the 5′ end and at the 3′ portion, respectively, seem to have evolved under purifying selection. Evidence of positive selection was found in non-repeat domains III, V and VII where a number of predicted HLA class I epitopes were identified. Amino acid substitutions in these predicted epitopes could alter predicted peptide binding affinity or abolish peptide epitope property, suggesting that polymorphism in these epitopes conferred host immune evasion. Further studies on PvMSP3F2 are warranted, particularly on interaction with host immune system and the potential role of this PvMSP3 protein member as a vaccine target.
Chemokines and Chemokine Receptors
2019, Clinical Immunology: Principles and Practice
Chemokines form a large family composed primarily of small secreted cytokine proteins that coordinate leukocyte trafficking by binding to seven-transmembrane (7TM) domain receptors. Chemokines mediate normal host defense and tissue repair; however, they may also support pathological immune responses, including chronic inflammation, autoimmunity, and cancer. The chemokine system is also a major target for immune system evasion or exploitation by pathogens (e.g., human immunodeficiency virus [HIV] and Plasmodium vivax). Increasingly, additional immunological and nonimmunological chemokine functions are being recognized. The nonimmunological functions can be beneficial, as in embryogenesis, or harmful, as in cancer. WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is the only known mendelian condition caused by mutations in a chemokine or chemokine receptor (the receptor CXCR4). Two chemokine receptor antagonists have been approved by the U.S. Food and Drug Administration (FDA) so far: maraviroc, a CCR5 antagonist, used in the treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and plerixafor, a CXCR4 antagonist, approved for hematopoietic stem cell mobilization for transplantation in cancer. This chapter will expand on these and other basic principles and clinical correlates of chemokine regulation of the immune system.
Genetic polymorphism and clustering of the Plasmodium cynomolgi Duffy binding protein 1 region II of recent macaque isolates from Peninsular Malaysia
2024, Parasitology Research

View all citing articles on Scopus

View full text

Invited reviewParasite ligand–host receptor interactions during invasion of erythrocytes by Plasmodium merozoites

Abstract

Introduction

Section snippets

The steps in the invasion process

Duffy blood group antigen as receptor in erythrocyte invasion

DBL family

Reticulocyte binding like (RBL) protein family

Redundancy in invasion of Plasmodium falciparum

Erythrocyte receptor polymorphism

Challenges for the future

Acknowledgements

Cell

Trends Parasitol.

Parasitol. Today

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Exp. Parasitol.

Transfus. Clin. Biol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Cell

Mol. Biochem. Parasitol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

J. Biol. Chem.

Mol. Biochem. Parasitol.

Blood

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

A family of erythrocyte binding proteins of malaria parasites

Proc. Natl Acad. Sci. USA

Structural alteration of the erythrocyte membrane during malarial parasite invasion and intraerythrocytic development

Ciba Found. Symp.

Erythrocyte entry by malarial parasites. A moving junction between erythrocyte and parasite

J. Cell Biol.

Freeze-fracture study on the erythrocyte membrane during malarial parasite invasion

J. Cell Biol.

Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3

Am. J. Trop. Med. Hyg.

The ultrastructure of red cell invasion in malaria infections: a review

Blood Cells

Plasmodium falciparum apical membrane antigen 1 (PfAMA-1) is translocated within micronemes along subpellicular microtubules during merozoite development

J. Cell Sci.

Invasion of erythrocytes

In vitro evaluation of the role of the Duffy blood group in erythrocyte invasion by Plasmodium vivax

J. Exp. Med.

Erythrocyte invasion phenotypes of Plasmodium falciparum in the Gambia

Infect. Immun.

Evidence for diversifying selection on erythrocyte-binding antigens of Plasmodium falciparum and P. vivax

Genetics

A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies

J. Exp. Med.

Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein

J. Exp. Med.

Transcripts of developmentally regulated Plasmodium falciparum genes quantified by real-time RT-PCR

Nucleic Acids Res.

Gerbich blood group system: a useful genetic marker in certain Melanesians of Papua and New Guinea

Nature

Studies on benign tertian malaria. IV. On the refractariness of negroes to inoculation with Plasmodium vivax

Am. J. Hyg.

Plasmodium chabaudi p68 serine protease activity required for merozoite entry into mouse erythrocytes

Proc. Natl Acad. Sci. USA

Invited review
Parasite ligand–host receptor interactions during invasion of erythrocytes by Plasmodium merozoites