Trends in Parasitology
Plasmodium rhoptries: how things went pear-shaped
Section snippets
The malaria burden
Plasmodium spp. are the causative agents of malaria, a disease of major medical and socioeconomic significance. The World Health Organization estimates that malaria parasites cause 300–500 million clinical infections and over two million deaths annually (http://www.who.int/malaria/docs/incidence_estimations2.pdf). The massive disease burden is inextricably linked to poverty, and in some areas causes a loss of as much as one percentage point of economic growth per year [1]. The emergence of
Plasmodium invasion – many hands make light work
Within its human host, Plasmodium spends most of its time residing within host cells. The extracellular phases of the life cycle are brief with sporozoites and merozoites designed for rapid invasion. Invasion begins when a parasite attaches to a host cell (hepatocyte or red blood cell), a process that depends on binding between molecules, usually proteins, on host and parasite surfaces. The parasite then reorients itself so that its apical end is in close proximity to the host cell membrane.
Rhoptry ultrastucture
Rhoptries have been visualised by electron microscopy (EM) in Plasmodium merozoites and sporozoites but seem to be absent from ookinetes. This difference could reflect the varied requirements of the different stages. Ookinetes rapidly penetrate the epithelial cells of the mosquito midgut and do not replicate within a PV. In contrast, merozoites and sporozoites develop into liver and red blood cell (RBC) schizonts, respectively, both enclosed by a PVM [9].
Rhoptry structure and development has
The rhoptry proteome – a collection of unusual proteins
Our knowledge of rhoptry components came initially from characterisation of the targets of monoclonal antibodies and human immune serum 28, 30, 31. This approach tended to favour the identification of proteins that were highly abundant or induced a robust antibody response during natural infection. Immunoprecipitation studies defined at least two protein complexes, the HMW complex composed of RhopH1, RhopH2 and RhopH3 and the low molecular weight (LMW) complex composed of RAP1, RAP2 and RAP3 32
Lipids – not just ‘membranes to go’
Early EM observations indicated that the rhoptries contain lipids, with numerous studies reporting the presence of internal membranes, lamellar whorls or multivesicular structures within the rhoptry body 23, 24, 65, 77. These whorls seemed to be discharged onto the host cell surface, inducing changes in its membrane structure. Furthermore, Mikkelsen et al. [78] showed that fluorescent lipid probes localised to the rhoptries were discharged during invasion and incorporated into the PV. These
Rhoptry function – more than meets the eye?
Although the molecular mechanisms remain only partially understood, the role of rhoptries in the invasion process has been well documented 85, 86. More recently, however, several investigators have proposed that the rhoptry is an organelle with dual functions, participating in both the exocytic and endocytic pathways. They argue that the rhoptry is not simply a secretory granule but is more akin to the secretory lysosome in higher eukaryotes 84, 87. Secretory lysosomes have been described in a
Concluding remarks
The invasion machinery of Plasmodium is an attractive candidate for therapeutic intervention. Invasion is a necessary step in the life cycle of the parasite, and effective inhibition of sporozoite or merozoite invasion would prevent parasite replication and clinical manifestations. The rhoptries participate in invasion, and rhoptry proteins show no similarity to host proteins, making them attractive drug targets. Furthermore, rhoptry proteins are exposed (briefly) to the immune system, and
Acknowledgements
The authors thank Robert Huestis for assistance with bioinformatic analysis. This work was supported by the National Health and Medical Research Council of Australia. L.M.K. and N.I.P. are supported by the Australian Postgraduate Award.
References (93)
- et al.
Host cell invasion by malaria parasites
Parasitol. Today
(2000) Characterization of a membrane-associated rhoptry protein of Plasmodium falciparum
J. Biol. Chem.
(2004)Apical organelles and host-cell invasion by Apicomplexa
Int. J. Parasitol.
(1998)Molecular and functional aspects of parasite invasion
Trends Parasitol.
(2004)Plasmodium falciparum: effects of membrane modulating agents on direct binding of rhoptry proteins to human erythrocytes
Exp. Parasitol.
(1995)Plasmodium falciparum: red blood cell binding studies using peptides derived from rhoptry-associated protein 2 (RAP2)
Biochimie
(2004)- et al.
A high molecular mass Plasmodium yoelii rhoptry protein binds to erythrocytes
Mol. Biochem. Parasitol.
(1996) A Reticulocyte Binding Protein complex of Plasmodium vivax merozoites
Cell
(1992)Complementation of a Toxoplasma gondii ROP1 knock-out mutant using phleomycin selection
Mol. Biochem. Parasitol.
(1995)Secretion from the rhoptries of Toxoplasma gondii during host-cell invasion
J. Ultrastruct. Res.
(1983)
Isolation of a Plasmodium falciparum rhoptry protein
Mol. Biochem. Parasitol.
Proteomic analysis of rhoptry organelles reveals many novel constituents for host–parasite interactions in Toxoplasma gondii
J. Biol. Chem.
A rhoptry antigen of Plasmodium falciparum contains conserved and variable epitopes recognized by inhibitory monoclonal antibodies
Mol. Biochem. Parasitol.
A component of an antigenic rhoptry complex of Plasmodium falciparum is modified after merozoite invasion
Mol. Biochem. Parasitol.
The 140/130/105 kilodalton protein complex in the rhoptries of Plasmodium falciparum consists of discrete polypeptides
Mol. Biochem. Parasitol.
Isolation and characterization of rhoptries of Plasmodium falciparum
Mol. Biochem. Parasitol.
The apicoplast: a plastid in Plasmodium falciparum and other Apicomplexan parasites
Int. Rev. Cytol.
Mix and match modules: structure and function of microneme proteins in apicomplexan parasites
Trends Parasitol.
Analysis of the processing of Plasmodium falciparum Rhoptry Associated Protein 1 and localization of Pr86 to schizont rhoptries and p67 to free merozoites
Mol. Biochem. Parasitol.
Identification of a stomatin orthologue in vacuoles induced in human erythrocytes by malaria parasites
J. Biol. Chem.
Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium yoelii
Mol. Biochem. Parasitol.
The Py235 proteins: glimpses into the versatility of a malaria multigene family
Microbes Infect.
The 235 kDa rhoptry protein of Plasmodium (yoelii) yoelii: function at the junction
Mol. Biochem. Parasitol.
Primary structure of a Plasmodium falciparum rhoptry antigen
Mol. Biochem. Parasitol.
Apical expression of three RhopH1/Clag proteins as components of the Plasmodium falciparum RhopH complex
Mol. Biochem. Parasitol.
A cDNA clone expressing a rhoptry protein of Plasmodium falciparum
Mol. Biochem. Parasitol.
Erythrocyte surface glycosylphosphatidyl inositol anchored receptor for the malaria parasite
Mol. Biochem. Parasitol.
A Plasmodium chabaudi protein contains a repetitive region with a predicted spectrin-like structure
Mol. Biochem. Parasitol.
Identification and disruption of a rhoptry-localized homologue of sodium hydrogen exchangers in Toxoplasma gondii
Int. J. Parasitol.
The secretary pathway of Plasmodium falciparum regulates transport of p82/RAP1 to the rhoptries
Mol. Biochem. Parasitol.
Identification and characterisation of RAMA homologues in rodent, simian and human malaria species
Mol. Biochem. Parasitol.
Plasmodium yoelii: brefeldin A-sensitive processing of proteins targeted to the rhoptries
Exp. Parasitol.
Processing of Toxoplasma ROP1 protein in nascent rhoptries
Mol. Biochem. Parasitol.
Characterization of PfRhop148, a novel rhoptry protein of Plasmodium falciparum
Mol. Biochem. Parasitol.
Characterization of trafficking pathways and membrane genesis in malaria-infected erythrocytes
Mol. Biochem. Parasitol.
Insights into unique physiological features of neutral lipids in Apicomplexa: from storage to potential mediation in parasite metabolic activities
Int. J. Parasitol.
Apical organelles of Apicomplexa: biology and isolation by subcellular fractionation
Mol. Biochem. Parasitol.
The apical organelles of malaria merozoites: host cell selection, invasion, host immunity and immune evasion
Microbes Infect.
Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method
Mol. Biochem. Parasitol.
The economic and social burden of malaria
Nature
Malaria in 2002
Nature
Antibodies to rhoptry-associated membrane antigen predict resistance to Plasmodium falciparum
J. Infect. Dis.
Update on the clinical development of candidate malaria vaccines
Am. J. Trop. Med. Hyg.
The ultrastructure of red cell invasion in malaria infections: a review
Blood Cells
Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes
EMBO J.
The Plasmodium falciparum genome – a blueprint for erythrocyte invasion
Science
Cited by (54)
The Lytic Cycle of Human Apicomplexan Parasites
2022, Encyclopedia of Cell Biology: Volume 1-6, Second EditionPlasmodium RON12 localizes to the rhoptry body in sporozoites
2019, Parasitology InternationalAdvances in the application of genetic manipulation methods to apicomplexan parasites
2017, International Journal for ParasitologyHuman erythrocyte band 3 functions as a receptor for the sialic acid-independent invasion of Plasmodium falciparum. Role of the RhopH3-MSP1 complex
2014, Biochimica et Biophysica Acta - Molecular Cell ResearchPlasmodium rhoptry proteins: Why order is important
2013, Trends in ParasitologyCitation Excerpt :Previously, the RAP complex has been implicated in invasion because antibodies and peptides specific for RAP1 can partially block in vitro invasion of RBCs. RAP1 is also immunogenic because anti-RAP1 can be detected in the sera of naturally infected hosts, although vaccines directed against this protein do not protect completely against challenge infection (reviewed in [9]). This lack of protection is consistent with what we now know about the sequence of invasion, which has revealed that ROPs are actually secreted into the PV/PVM after formation of the TJ [53].