Plasmodium rhoptries: how things went pear-shaped

https://doi.org/10.1016/j.pt.2006.04.001Get rights and content

Plasmodium parasites have three sets of specialised secretory organelles at the apical end of their invasive forms – rhoptries, micronemes and dense granules. The contents of these organelles are responsible for or contribute to host cell invasion and modification, and at least four apical proteins are leading vaccine candidates. Given the unusual nature of Plasmodium invasion, it is not surprising that unique proteins are involved in this process. Nowhere is this more evident than in rhoptries. We have collated data from several recent studies to compile a rhoptry proteome. Discussion is focussed here on rhoptry content and function.

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)

  • A.A. Holder

    Isolation of a Plasmodium falciparum rhoptry protein

    Mol. Biochem. Parasitol.

    (1985)
  • P.J. Bradley

    Proteomic analysis of rhoptry organelles reveals many novel constituents for host–parasite interactions in Toxoplasma gondii

    J. Biol. Chem.

    (2005)
  • L. Schofield

    A rhoptry antigen of Plasmodium falciparum contains conserved and variable epitopes recognized by inhibitory monoclonal antibodies

    Mol. Biochem. Parasitol.

    (1986)
  • S. Lustigman

    A component of an antigenic rhoptry complex of Plasmodium falciparum is modified after merozoite invasion

    Mol. Biochem. Parasitol.

    (1988)
  • J.A. Cooper

    The 140/130/105 kilodalton protein complex in the rhoptries of Plasmodium falciparum consists of discrete polypeptides

    Mol. Biochem. Parasitol.

    (1988)
  • Z. Etzion

    Isolation and characterization of rhoptries of Plasmodium falciparum

    Mol. Biochem. Parasitol.

    (1991)
  • B.J. Foth et al.

    The apicoplast: a plastid in Plasmodium falciparum and other Apicomplexan parasites

    Int. Rev. Cytol.

    (2003)
  • F.M. Tomley et al.

    Mix and match modules: structure and function of microneme proteins in apicomplexan parasites

    Trends Parasitol.

    (2001)
  • R.F. Howard

    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.

    (1998)
  • N.L. Hiller

    Identification of a stomatin orthologue in vacuoles induced in human erythrocytes by malaria parasites

    J. Biol. Chem.

    (2003)
  • I.T. Ling

    Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium yoelii

    Mol. Biochem. Parasitol.

    (2003)
  • A.C. Gruner

    The Py235 proteins: glimpses into the versatility of a malaria multigene family

    Microbes Infect.

    (2004)
  • S.M. Khan

    The 235 kDa rhoptry protein of Plasmodium (yoelii) yoelii: function at the junction

    Mol. Biochem. Parasitol.

    (2001)
  • H.J. Brown et al.

    Primary structure of a Plasmodium falciparum rhoptry antigen

    Mol. Biochem. Parasitol.

    (1991)
  • O. Kaneko

    Apical expression of three RhopH1/Clag proteins as components of the Plasmodium falciparum RhopH complex

    Mol. Biochem. Parasitol.

    (2005)
  • R.L. Coppel

    A cDNA clone expressing a rhoptry protein of Plasmodium falciparum

    Mol. Biochem. Parasitol.

    (1987)
  • T. Rungruang

    Erythrocyte surface glycosylphosphatidyl inositol anchored receptor for the malaria parasite

    Mol. Biochem. Parasitol.

    (2005)
  • E.B. Werner

    A Plasmodium chabaudi protein contains a repetitive region with a predicted spectrin-like structure

    Mol. Biochem. Parasitol.

    (1998)
  • A.O. Karasov

    Identification and disruption of a rhoptry-localized homologue of sodium hydrogen exchangers in Toxoplasma gondii

    Int. J. Parasitol.

    (2005)
  • R.F. Howard et al.

    The secretary pathway of Plasmodium falciparum regulates transport of p82/RAP1 to the rhoptries

    Mol. Biochem. Parasitol.

    (1995)
  • A.E. Topolska

    Identification and characterisation of RAMA homologues in rodent, simian and human malaria species

    Mol. Biochem. Parasitol.

    (2004)
  • S.A. Ogun et al.

    Plasmodium yoelii: brefeldin A-sensitive processing of proteins targeted to the rhoptries

    Exp. Parasitol.

    (1994)
  • D. Soldati

    Processing of Toxoplasma ROP1 protein in nascent rhoptries

    Mol. Biochem. Parasitol.

    (1998)
  • C.A. Lobo

    Characterization of PfRhop148, a novel rhoptry protein of Plasmodium falciparum

    Mol. Biochem. Parasitol.

    (2003)
  • B. Pouvelle

    Characterization of trafficking pathways and membrane genesis in malaria-infected erythrocytes

    Mol. Biochem. Parasitol.

    (1994)
  • I. Coppens et al.

    Insights into unique physiological features of neutral lipids in Apicomplexa: from storage to potential mediation in parasite metabolic activities

    Int. J. Parasitol.

    (2005)
  • M.J. Blackman et al.

    Apical organelles of Apicomplexa: biology and isolation by subcellular fractionation

    Mol. Biochem. Parasitol.

    (2001)
  • P. Preiser

    The apical organelles of malaria merozoites: host cell selection, invasion, host immunity and immune evasion

    Microbes Infect.

    (2000)
  • C.J. Tonkin

    Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method

    Mol. Biochem. Parasitol.

    (2004)
  • J. Sachs et al.

    The economic and social burden of malaria

    Nature

    (2002)
  • B. Greenwood et al.

    Malaria in 2002

    Nature

    (2002)
  • C.P. Nixon

    Antibodies to rhoptry-associated membrane antigen predict resistance to Plasmodium falciparum

    J. Infect. Dis.

    (2005)
  • W.R. Ballou

    Update on the clinical development of candidate malaria vaccines

    Am. J. Trop. Med. Hyg.

    (2004)
  • L.H. Bannister et al.

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

    Blood Cells

    (1990)
  • M.T. Duraisingh

    Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes

    EMBO J.

    (2003)
  • A.F. Cowman et al.

    The Plasmodium falciparum genome – a blueprint for erythrocyte invasion

    Science

    (2002)
  • Cited by (54)

    • The Lytic Cycle of Human Apicomplexan Parasites

      2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition
    • Plasmodium rhoptry proteins: Why order is important

      2013, Trends in Parasitology
      Citation 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].

    View all citing articles on Scopus
    View full text