Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Common infection strategies of pathogenic eukaryotes

Nature Reviews Microbiology volume 4, pages 922–931 (2006)Cite this article

Key Points

  • Divergent eukaryotic pathogens use common host-targeting signals in both animal and plant hosts. The first identification of a eukaryotic pathogen host-targeting signal was made in the human malaria parasite Plasmodium falciparum. This led to the first definition of the host-targeted 'secretome' of a eukaryotic pathogen. A functionally equivalent signal is conserved in the Irish potato famine pathogen Phytophthora infestans, showing that the host-targeting signal is shared in an apicomplexan and an oomycete.

  • The size and complexity of the predicted host-targeted secretome is significantly greater than that predicted for signal-mediated effectors in prokaryotic pathogens. The predicted involvement of hundreds of effectors indicates diverse mechanisms are involved in host remodelling by animal and plant pathogens. Analyses of common and contrasting domains in the effector secretomes reveal ABC transporters, post-translational or protein folding events in host remodelling, combined with expansions in specific gene families linked to virulence and evolution.

  • Analyses of the invasion mechanisms and secreted proteases of P. infestans and P. falciparum indicate a broader similarity in a wide range of pathogenicity mechanisms between animal and plant parasites than is currently appreciated.

  • Phylogenetic trees highlighting the major groups of animal and plant pathogens show that apicomplexans and oomycetes are divergent but more related to each other than to other pathogen groups, such as fungi, suggesting the need for a re-evaluation of their similarities, based on phylogeny and cellular similarities.

  • With the emerging genomics resources for eukaryotic parasites, it is important to appreciate that, like prokaryotes, similarities exist across divergent eukaryotic microorganisms and these could be exploited to elucidate new concepts in eukaryotic pathogenesis and potential new treatments for difficult infections. We are on the cusp of unique opportunities for the comparative genomics of eukaryotic microorganisms and these will be augmented by an understanding of common pathogenicity mechanisms in divergent species and an appreciation how such conserved mechanisms manifest themselves.

Abstract

Pathogenic eukaryotes belong to several distinct phylogenetic lineages and have evolved the ability to colonize a range of hosts, including animals and plants. Pathogenic lifestyles have evolved repeatedly in eukaryotes, indicating that unique molecular processes are involved in host infection. However, evidence is now emerging that divergent eukaryotic pathogens might share common mechanisms of pathogenicity. The results from recent studies demonstrate that Plasmodium falciparum and Phytophthora infestans use equivalent host-targeting signals to deliver virulence adhesins and avirulence gene products into human and plant cells, respectively. Remodelling of host cells by different eukaryotic pathogens might therefore share some common features.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Erythrocytic infection by malarial parasites.
Figure 2: Infection of host plants by Phytophthora infestans.
Figure 3: Intracellular infection by Phytophthora infestans and Plasmodium falciparum.
Figure 4: Comparative analysis of the host-targeting signal in Plasmodium falciparum and Phytophthora spp.
Figure 5: Families of putative host-targeted heat shock protein DNAJ-domain-containing proteins in Plasmodium species.
Figure 6: Phylogenetic relationships among eukaryotes, showing the major groups of parasites and pathogens.

Similar content being viewed by others

References

  1. Preston, G. M., Studholme, D. J. & Caldelari, I. Profiling the secretomes of plant pathogenic Proteobacteria. FEMS Microbiol. Rev. 29, 331–360 (2005).

    Article  CAS  Google Scholar 

  2. Christie, P. J. et al. Biogenesis, architecture, and function of bacterial type IV secretion systems. Annu. Rev. Microbiol. 59, 451–485 (2005).

    Article  CAS  Google Scholar 

  3. Lammertyn, E. & Anne, J. Protein secretion in Legionella pneumophila and its relation to virulence. FEMS Microbiol. Lett. 238, 273–279 (2004).

    CAS  PubMed  Google Scholar 

  4. Journet, L., Hughes, K. T. & Cornelis, G. R. Type III secretion: a secretory pathway serving both motility and virulence. Mol. Membr. Biol. 22, 41–50 (2005).

    Article  CAS  Google Scholar 

  5. Miller, L. H. et al. The pathogenic basis of malaria. Nature 415, 673–679 (2002).

    Article  CAS  Google Scholar 

  6. Haldar, K. et al. Protein and lipid trafficking induced in erythrocytes infected by malaria parasites. Cell. Microbiol. 4, 383–395 (2002).

    Article  CAS  Google Scholar 

  7. Su, X.-Z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100 (1995).

    Article  CAS  Google Scholar 

  8. Fernandez, V. et al. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum-infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. J. Exp. Med. 190, 1393–1404 (1999).

    Article  CAS  Google Scholar 

  9. Cooke, B. M. et al. Protein trafficking in Plasmodium falciparum-infected red blood cells. Trends Parasitol. 20, 581–589 (2004).

    Article  CAS  Google Scholar 

  10. Baldauf, S. L. et al. A kingdom-level phylogeny of eukaryotes based on combined protein data. Science 290, 972–977 (2000).

    Article  CAS  Google Scholar 

  11. Kamoun, S. Molecular genetics of pathogenic oomycetes. Euk. Cell 2, 191–199 (2003).

    Article  CAS  Google Scholar 

  12. Huitema, E. et al. Linking sequence to phenotype in Phytophthora-plant interactions. Trends Microbiol. 12, 193–200 (2004).

    Article  CAS  Google Scholar 

  13. Ellis, J., Catanzariti, A. M. & Dodds, P. The problem of how fungal and oomycete avirulence proteins enter plant cells. Trends Plant Sci. 11, 61–63 (2006).

    Article  CAS  Google Scholar 

  14. Kamoun, S. A catalogue of the effector secretome of plant pathogenic oomycetes. Annu. Rev. Phytopathol. 44, 41–60 (2006). This review highlights recent findings on the structure of oomycete effectors, such as the RxLR effectors.

    Article  CAS  Google Scholar 

  15. Birch, P. R. et al. Trafficking arms: oomycete effectors enter host plant cells. Trends Microbiol. 14, 8–11 (2006).

    Article  CAS  Google Scholar 

  16. Allen, R. L. et al. Host-parasite coevolutionary conflict between Arabidopsis and downy mildew. Science 306, 1957–1960 (2004). The cloning of Hyaloperonospora parasitica ATR1 along with other oomycete avirulence genes resulted in the discovery of the conserved RxLR motif.

    Article  CAS  Google Scholar 

  17. Rehmany, A. P. et al. Differential recognition of highly divergent downy mildew avirulence gene alleles by RPP1 resistance genes from two Arabidopsis lines. Plant Cell 17, 1839–1850 (2005).

    Article  CAS  Google Scholar 

  18. Armstrong, M. R. et al. An ancestral oomycete locus contains late blight avirulence gene Avr3a, encoding a protein that is recognized in the host cytoplasm. Proc. Natl Acad. Sci. USA 102, 7766–7771 (2005).

    Article  CAS  Google Scholar 

  19. Lopez-Estrano, C. et al. Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum-infected erythrocytes. Proc. Natl Acad. Sci. USA 100, 12402–12407 (2003). This study first defined minimal vacuolar translocation sequences (VTS) of about 35–40 amino acids necessary and sufficient for the export of P. falciparum proteins to the host erythrocyte.

    Article  CAS  Google Scholar 

  20. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004). This study along with Ref. 21 simultaneously described a host-cell-targeting signal present in hundreds of parasite secretory proteins and thereby predicted a 'secretome' for malarial infection.

    Article  CAS  Google Scholar 

  21. Marti, M. et al. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004).

    Article  CAS  Google Scholar 

  22. Schwarze, S. R. et al. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).

    Article  CAS  Google Scholar 

  23. Muller, M. & Klosgen, R. B. The Tat pathway in bacteria and chloroplasts. Mol. Membr. Biol. 22, 113–121 (2005).

    Article  Google Scholar 

  24. Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006).

    Article  Google Scholar 

  25. Bos, J. I. et al. The C-terminal half of Phytophthora infestans RXLR effector AVR3a is sufficient to trigger R3a-mediated hypersensitivity and suppress INF1-induced cell death in Nicotiana benthamiana. Plant J. 48, 165–176 (2006).

    Article  CAS  Google Scholar 

  26. Bhattacharjee, S. et al. The malarial host-targeting signal is conserved in the Irish potato famine pathogen. PLoS Pathog. 2, e50 (2006). This study established the molecular equivalence between host-targeting signals of Plasmodium and Phytopthora species.

    Article  Google Scholar 

  27. Neduva, V. & Russell, R. B. Linear motifs: evolutionary interaction switches. FEBS Lett. 579, 3342–3345 (2005).

    Article  CAS  Google Scholar 

  28. Ward, P. et al. Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics 5, 79 (2004).

    Article  Google Scholar 

  29. Sam-Yellowe, T. Y. et al. A Plasmodium gene family encoding Maurer's cleft membrane proteins: structural properties and expression profiling. Genome Res. 14, 1052–1059 (2004).

    Article  CAS  Google Scholar 

  30. Schneider, A. G. & Mercereau-Puijalon, O. A new Apicomplexa-specific protein kinase family: multiple members in Plasmodium falciparum, all with an export signature. BMC Genomics 6, 30 (2005).

    Article  Google Scholar 

  31. Janssen, C. S. et al. Plasmodium interspersed repeats: the major multigene superfamily of malaria parasites. Nucleic Acids Res. 32, 5712–5720 (2004).

    Article  CAS  Google Scholar 

  32. Kooij, T. W. et al. A Plasmodium whole-genome synteny map: indels and synteny breakpoints as foci for species-specific genes. PLoS Pathog. 1, e44 (2005).

    Article  Google Scholar 

  33. Brunner, F. et al. Pep-13, a plant defense-inducing pathogen-associated pattern from Phytophthora transglutaminases. EMBO J. 21, 6681–6688 (2002).

    Article  CAS  Google Scholar 

  34. Sibley, L. D. Intracellular parasite invasion strategies. Science 304, 248–253 (2004). This is an excellent review for apicomplexan invasion strategies.

    Article  CAS  Google Scholar 

  35. Judelson, H. S. & Blanco, F. A. The spores of Phytophthora: weapons of the plant destroyer. Nature Rev. Microbiol. 3, 47–58 (2005).

    Article  CAS  Google Scholar 

  36. Robold, A. V. & Hardham, A. R. During attachment Phytophthora spores secrete proteins containing thrombospondin type 1 repeats. Curr. Genet. 47, 307–315 (2005). Shows that PcVsv1, a 260-kDa protein secreted by Phytophthora spores is similar to apicomplexan adhesins.

    Article  CAS  Google Scholar 

  37. Deng, M. et al. Cryptosporidium parvum genes containing thrombospondin type 1 domains. Infect. Immun. 70, 6987–6995 (2002).

    Article  CAS  Google Scholar 

  38. Kappe, S. H., Buscaglia, C. A. & Nussenzweig, V. Plasmodium sporozoite molecular cell biology. Annu. Rev. Cell. Dev. Biol. 20, 29–59 (2004).

    Article  CAS  Google Scholar 

  39. Kappe, S. et al. Conservation of a gliding motility and cell invasion machinery in Apicomplexan parasites. J. Cell Biol. 147, 937–944 (1999).

    Article  CAS  Google Scholar 

  40. Sultan, A. A. et al. TRAP is necessary for gliding motility and infectivity of Plasmodium sporozoites. Cell 90, 511–522 (1997).

    Article  CAS  Google Scholar 

  41. Menard, R. Gliding motility and cell invasion by Apicomplexa: insights from the Plasmodium sporozoite. Cell. Microbiol. 3, 63–73 (2001).

    Article  CAS  Google Scholar 

  42. Baum, J. et al. A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites. J. Biol. Chem. 281, 5197–5208 (2006).

    Article  CAS  Google Scholar 

  43. Brecht, S. et al. The Toxoplasma micronemal protein MIC4 is an adhesin composed of six conserved apple domains. J. Biol. Chem. 276, 4119–4127 (2001).

    Article  CAS  Google Scholar 

  44. Brown, P. J. et al. A microneme protein from Eimeria tenella with homology to the Apple domains of coagulation factor XI and plasma pre-kallikrein. Mol. Biochem. Parasitol. 107, 91–102 (2000).

    Article  CAS  Google Scholar 

  45. Brown, P.J. et al. Domains of invasion organelle proteins from apicomplexan parasites are homologous with the Apple domains of blood coagulation factor XI and plasma pre-kallikrein and are members of the PAN module superfamily. FEBS Lett. 497, 31–38 (2001).

    Article  CAS  Google Scholar 

  46. Pizarro, J.C. et al. Crystal structure of the malaria vaccine candidate apical membrane antigen 1. Science 308, 408–411 (2005). This is an important paper for the development of a malaria vaccine.

    Article  CAS  Google Scholar 

  47. Mital, J. et al. Conditional expression of Toxoplasma gondii apical membrane antigen-1 (TgAMA1) demonstrates that TgAMA1 plays a critical role in host cell invasion. Mol. Biol. Cell 16, 4341–4349 (2005).

    Article  CAS  Google Scholar 

  48. Mullen, G. E. et al. Enhancement of functional antibody responses to AMA1-C1/Alhydrogel, a Plasmodium falciparum malaria vaccine, with CpG oligodeoxynucleotide. Vaccine 24, 2497–2505 (2006).

    Article  CAS  Google Scholar 

  49. Gaulin, E. et al. The CBEL glycoprotein of Phytophthora parasitica var. nicotianae is involved in cell wall deposition and adhesion to cellulosic substrates. J. Cell Sci. 115, 4565–4575 (2002).

    Article  CAS  Google Scholar 

  50. Torto, T. A. et al. EST mining and functional expression assays identify extracellular effector proteins from the plant pathogen Phytophthora. Genome Res. 13, 1675–1685 (2003).

    Article  CAS  Google Scholar 

  51. Pszenny, V. et al. Molecular cloning, sequencing and expression of a serine proteinase inhibitor gene from Toxoplasma gondii. Mol. Biochem. Parasitol. 107, 241–249 (2000).

    Article  CAS  Google Scholar 

  52. Lindh, J. G. et al. A protease inhibitor associated with the surface of Toxoplasma gondii. Mol. Biochem. Parasitol. 116, 137–145 (2001).

    Article  CAS  Google Scholar 

  53. Morris, M. T. et al. Neospora caninum expresses an unusual single-domain Kazal protease inhibitor that is discharged into the parasitophorous vacuole. Int. J. Parasitol. 34, 693–701 (2004).

    Article  CAS  Google Scholar 

  54. Bruno, S. et al. Identification and characterization of serine proteinase inhibitors from Neospora caninum. Mol. Biochem. Parasitol. 136, 101–107 (2004).

    Article  CAS  Google Scholar 

  55. Abrahamsen, M. S. et al. Complete genome sequence of the apicomplexan, Cryptosporidium parvum. Science 304, 441–445 (2004).

    Article  CAS  Google Scholar 

  56. Tian, M. et al. A Kazal-like extracellular serine protease inhibitor from Phytophthora infestans targets the tomato pathogenesis-related protease P69B. J. Biol. Chem. 279, 26370–26377 (2004). In this first report of a protease inhibitor from a plant pathogenic microorganism, the similarity with animal parasites is highlighted.

    Article  CAS  Google Scholar 

  57. Santos, C. C. et al. Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells. J. Cell Sci. 118, 901–915 (2005).

    Article  CAS  Google Scholar 

  58. Besteiro, S., Coombs, G. H. & Mottram, J. C. A potential role for ICP, a leishmanial inhibitor of cysteine peptidases, in the interaction between host and parasite. Mol. Microbiol. 54, 1224–1236 (2004).

    Article  CAS  Google Scholar 

  59. Rigden, D.J., Mosolov, V. V. & Galperin, M. Y. Sequence conservation in the chagasin family suggests a common trend in cysteine proteinase binding by unrelated protein inhibitors. Protein Sci. 11, 1971–1977 (2002).

    Article  CAS  Google Scholar 

  60. Torto-Alalibo, T. et al. Expressed sequence tags from the oomycete fish pathogen Saprolegnia parasitica reveal putative virulence factors. BMC Microbiol. 5, 46 (2005).

    Article  Google Scholar 

  61. Win, J. et al. Computational and comparative analyses of 150 full-length cDNA sequences from the oomycete plant pathogen Phytophthora infestans. Fungal Genet. Biol. 43, 20–33 (2006).

    Article  CAS  Google Scholar 

  62. Orbach, M. J. et al. A telomeric avirulence gene determines efficacy for the rice blast resistance gene Pi-ta. Plant Cell 12, 2019–2032 (2000).

    Article  CAS  Google Scholar 

  63. Dodds, P. N. et al. The Melampsora lini AvrL567 avirulence genes are expressed in haustoria and their products are recognized inside plant cells. Plant Cell 16, 755–768 (2004).

    Article  CAS  Google Scholar 

  64. Kemen, E. et al. Identification of a protein from rust fungi transferred from haustoria into infected plant cells. Mol. Plant-Microbe Interact. 18, 1130–1139 (2005).

    Article  CAS  Google Scholar 

  65. Embley, T. M. & Martin, W. Eukaryotic evolution, changes and challenges. Nature 440, 623–630 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health (K.H.), American Heart Foundation (NLH) and the National Science Foundation (S.K.).

Author information

Authors and Affiliations

  1. Departments of Pathology and Microbiology-Immunology, Northwestern University, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Kasturi Haldar, N. Luisa Hiller, Souvik Bhattacharje & Christiaan van Ooij

  2. Department of Plant Pathology, The Ohio State University, Ohio Agricultural Research and Development Center, Wooster, 44691, Ohio, USA

    Sophien Kamoun

Authors
  1. Kasturi Haldar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sophien Kamoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Luisa Hiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Souvik Bhattacharje
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christiaan van Ooij
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kasturi Haldar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Genome Project

Cryptosporidium parvum

Neospora caninum

Phytophthora infestans

Phytophthora ramorum

Phytophthora sojae

Plasmodium berghei

Plasmodium falciparum

Plasmodium vivax

Plasmodium yoelii

Toxoplasma gondii

FURTHER INFORMATION

Kasturi Haldar's homepage

PlasmoHT

The Institute for Genomic Research

Glossary

Avirulence protein

An effector protein of plant pathogens that triggers disease resistance.

Parasitophorous vacuole

A vacuole within the host cell in which the parasite resides.

Maurer's clefts

Single-membrane-limited structures in the erythrocyte cytoplasm.

Biotrophic

A biotrophic pathogen invades host tissue without killing host cells and feeds on living cells.

Sporangium

A sac-like structure that is capable of converting its cytoplasm into multiple spores.

Zoospore

A flagellated, wall-less spore, specialized for dispersal.

Isoflavones

Specialized polyphenolic metabolites produced by plants of the legume family.

Appressoria

Specialized infection structures of oomycete and fungal plant pathogens that enable host penetration.

Hypersensitive response

A programmed cell-death response of plants that is associated with resistance.

General secretory pathway

Pathway for protein secretion through the endoplasmic reticulum and Golgi to the plasma membrane.

Twin-arginine transport

(TAT). A protein transport system that transports proteins across membranes in a fully folded state.

Syntenous orthologue

An orthologue in which the gene locus is conserved among species.

Micronemes

Micronemes are located at the apical end of all three invasive stages of apicomplexan parasites and have an important role in gliding motility, host-cell adhesion and invasion.

Rhoptries

Rhoptries are located at the apical end of certain invasive stages of apicomplexan parasites, and have an important role in host-cell adhesion and invasion, and in the establishment of the parasitophorous vacuole.

Dense granules

Secretory granules, the contents of which are released from the parasites after discharge from the rhoptries.

Gliding motility

A form of substrate-dependent locomotion in which the parasite maintains a fixed shape.

Haustoria

Specialized infection structures of biotrophic oomycete and fungal plant pathogens that invaginate into plant cells but remain enveloped by a modified host-cell membrane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haldar, K., Kamoun, S., Hiller, N. et al. Common infection strategies of pathogenic eukaryotes. Nat Rev Microbiol 4, 922–931 (2006). https://doi.org/10.1038/nrmicro1549

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro1549

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing