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:

Evasion of innate immunity by parasitic protozoa

Nature Immunology volume 3, pages 1041–1047 (2002)Cite this article

Abstract

Parasitic protozoa are a major cause of global infectious disease. These eukaryotic pathogens have evolved with the vertebrate immune system and typically produce long-lasting chronic infections. A critical step in their host interaction is the evasion of innate immune defenses. The ability to avoid attack by humoral effector mechanisms, such as complement lysis, is of particular importance to extracellular parasites, whereas intracellular protozoa must resist killing by lysosomal enzymes and toxic metabolites. They do so by remodeling the phagosomal compartments in which they reside and by interfering with signaling pathways that lead to cellular activation. In addition, there is growing evidence that protozoan pathogens modify the antigen-presenting and immunoregulatory functions of dendritic cells, a process that facilitates their evasion of both innate and adaptive immunity.

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: Remodeling of macrophage intracellular compartments by parasitic protozoa.
Figure 2: Inhibition of macrophage signaling pathways.

Similar content being viewed by others

References

  1. Pearce, E.J., Scott, P.A. & Sher, A. in Fundamental immunology (ed. Paul, W.) 1271–1294 (Lippincott-Raven, Philadelphia, 1999).

    Google Scholar 

  2. Borst, P. et al. Antigenic variation in trypanosomes. Arch. Med. Res. 27, 379–388 (1996).

    CAS  PubMed  Google Scholar 

  3. Nash, T.E. Surface antigenic variation in Giardia lamblia. Mol. Microbiol. 45, 585–590 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Kyes, S., Horrocks, P. & Newbold, C. Antigenic variation at the infected red cell surface in malaria. Annu. Rev. Microbiol. 55, 673–707 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194, 1497–506 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hunter, C. & Sher, A. in Immunology of Infectious Diseases (eds. Kaufman, S., Sher, A. & Ahmed, R.) 111–126 (ASM Press, Washington DC, 2001).

    Google Scholar 

  7. Joiner, K.A. Complement evasion by bacteria and parasites. Annu. Rev. Microbiol. 42, 201–230 (1988).

    Article  CAS  PubMed  Google Scholar 

  8. Norris, K.A., Bradt, B., Cooper, N.R. & So, M. Characterization of a Trypanosoma cruzi C3 binding protein with functional and genetic similarities to the human complement regulatory protein, decay-accelerating factor. J. Immunol. 147, 2240–2247 (1991).

    CAS  PubMed  Google Scholar 

  9. Norris, K.A. Stable transfection of Trypanosoma cruzi epimastigotes with the trypomastigote-specific complement regulatory protein cDNA confers complement resistance. Infect. Immun. 66, 2460–2465 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Puentes, S.M., Da Silva, R.P., Sacks, D.L., Hammer, C.H. & Joiner, K.A. Serum resistance of metacyclic stage Leishmania major promastigotes is due to release of C5b-9. J. Immunol. 145, 4311–4316 (1990).

    CAS  PubMed  Google Scholar 

  11. McConville, M.J., Turco, S.J., Ferguson, M.A. & Sacks, D.L. Developmental modification of lipophosphoglycan during the differentiation of Leishmania major promastigotes to an infectious stage. EMBO J. 11, 3593–3600 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brittingham, A. et al. Role of the Leishmania surface protease gp63 in complement fixation, cell adhesion, and resistance to complement-mediated lysis. J. Immunol. 155, 3102–3111 (1995).

    CAS  PubMed  Google Scholar 

  13. Mosser, D.M. & Edelson, P.J. The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of Leishmania promastigotes. J. Immunol. 135, 2785–2789 (1985).

    CAS  PubMed  Google Scholar 

  14. Spath, G.F. et al. Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proc. Natl. Acad. Sci. USA 97, 9258–9263 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Joshi, P.B., Kelly, B.L., Kamhawi, S., Sacks, D.L. & McMaster, W.R. Targeted gene deletion in Leishmania major identifies leishmanolysin (GP63) as a virulence factor. Mol. Biochem. Parasitol. 120, 33–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Raper, J., Portela, M.P., Lugli, E., Frevert, U. & Tomlinson, S. Trypanosome lytic factors: novel mediators of human innate immunity. Curr. Opin. Microbiol. 4, 402–408 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Hajduk, S.L. et al. Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein. J. Biol. Chem. 264, 5210–5217 (1989).

    Article  CAS  PubMed  Google Scholar 

  18. Smith, A.B., Esko, J.D. & Hajduk, S.L. Killing of trypanosomes by the human haptoglobin-related protein. Science 268, 284–286 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Raper, J., Fung, R., Ghiso, J., Nussenzweig, V. & Tomlinson, S. Characterization of a novel trypanosome lytic factor from human serum. Infect. Immun. 67, 1910–1916 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. De Greef, C. & Hamers, R. The serum resistance-associated (SRA) gene of Trypanosoma brucei rhodesiense encodes a variant surface glycoprotein-like protein. Mol. Biochem. Parasitol. 68, 277–284 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Xong, H.V. et al. A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense. Cell 95, 839–846 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Milner, J.D. & Hajduk, S.L. Expression and localization of serum resistance associated protein in Trypanosoma brucei rhodesiense. Mol. Biochem. Parasitol. 104, 271–283 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Sibley, L.D. & Andrews, N.W. Cell invasion by un-palatable parasites. Traffic 1, 100–106 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Mordue, D.G., Desai, N., Dustin, M. & Sibley, L.D. Invasion by Toxoplasma gondii establishes a moving junction that selectively excludes host cell plasma membrane proteins on the basis of their membrane anchoring. J. Exp. Med. 190, 1783–1792 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lingelbach, K. & Joiner, K.A. The parasitophorous vacuole membrane surrounding Plasmodium and Toxoplasma: an unusual compartment in infected cells. J. Cell Sci. 111, 1467–1475 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Andrews, N.W., Abrams, C.K., Slatin, S.L. & Griffiths, G.A T. cruzi-secreted protein immunologically related to the complement component C9: evidence for membrane pore–forming activity at low pH. Cell 61, 1277–1287 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Hall, B.F., Webster, P., Ma, A.K., Joiner, K.A. & Andrews, N.W. Desialylation of lysosomal membrane glycoproteins by Trypanosoma cruzi: a role for the surface neuraminidase in facilitating parasite entry into the host cell cytoplasm. J. Exp. Med. 176, 313–325 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Ming, M., Ewen, M.E. & Pereira, M.E. Trypanosome invasion of mammalian cells requires activation of the TGF-β signaling pathway. Cell 82, 287–296 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Rittig, M.G. & Bogdan, C. Leishmania-host-cell interaction: complexities and alternative views. Parasitol. Today 16, 292–297 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Alexander, J. & Russell, D.G. The interaction of Leishmania species with macrophages. Adv. Parasitol. 31, 175–254 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Courret, N. et al. Biogenesis of Leishmania-harbouring parasitophorous vacuoles following phagocytosis of the metacyclic promastigote or amastigote stages of the parasites. J. Cell Sci. 115, 2303–2316 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Desjardins, M. & Descoteaux, A. Inhibition of phagolysosomal biogenesis by the Leishmania lipophosphoglycan. J. Exp. Med. 185, 2061–2068 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dermine, J.F., Scianimanico, S., Prive, C., Descoteaux, A. & Desjardins, M. Leishmania promastigotes require lipophosphoglycan to actively modulate the fusion properties of phagosomes at an early step of phagocytosis. Cell Microbiol. 2, 115–126 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Ilg, T., Demar, M. & Harbecke, D. Phosphoglycan repeat-deficient Leishmania mexicana parasites remain infectious to macrophages and mice. J. Biol. Chem. 276, 4988–4997 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Nathan, C. & Shiloh, M.U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. USA 97, 8841–8848 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schwarzer, E. et al. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J. Exp. Med. 176, 1033–1041 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Schwarzer, E., Turrini, F., Giribaldi, G., Cappadoro, M. & Arese, P. Phagocytosis of P. falciparum malarial pigment hemozoin by human monocytes inactivates monocyte protein kinase C. Biochim. Biophys. Acta 1181, 51–54 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Moore, K.J., Labrecque, S. & Matlashewski, G. Alteration of Leishmania donovani infection levels by selective impairment of macrophage signal transduction. J. Immunol. 150, 4457–4465 (1993).

    CAS  PubMed  Google Scholar 

  39. Olivier, M., Brownsey, R.W. & Reiner, N.E. Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C. Proc. Natl. Acad. Sci. USA 89, 7481–7485 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Descoteaux, A., Matlashewski, G. & Turco, S.J. Inhibition of macrophage protein kinase C-mediated protein phosphorylation by Leishmania donovani lipophosphoglycan. J. Immunol. 149, 3008–3015 (1992).

    CAS  PubMed  Google Scholar 

  41. McDowell, M.A. & Sacks, D.L. Inhibition of host cell signal transduction by Leishmania: observations relevant to the selective impairment of IL-12 responses. Curr. Opin. Microbiol. 2, 438–443 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Piedrafita, D. et al. Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans. Eur. J. Immunol. 29, 235–244 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Nandan, D. & Reiner, N.E. Attenuation of γ interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1. Infect. Immun. 63, 4495–4500 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Blanchette, J., Racette, N., Faure, R., Siminovitch, K.A. & Olivier, M. Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-γ-triggered Jak2 activation. Eur J. Immunol. 29, 3737–3744 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Forget, G. et al. Role of host phosphotyrosine phosphatase SHP-1 in the development of murine Leishmaniasis. Eur. J. Immunol. 31, 3185–3196 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Marth, T. & Kelsall, B.L. Regulation of interleukin-12 by complement receptor 3 signaling. J. Exp. Med. 185, 1987–1995 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Giese, N.A. et al. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535–1546 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Xu, X. et al. Down-regulation of IL-12 p40 gene in Plasmodium berghei-infected mice. J. Immunol. 167, 235–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Butcher, B.A., Kim, L., Johnson, P.F. & Denkers, E.Y. Toxoplasma gondii tachyzoites inhibit proinflammatory cytokine induction in infected macrophages by preventing nuclear translocation of the transcription factor NF-κB. J. Immunol. 167, 2193–2201 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Shapira, S., Speirs, K., Gerstein, A., Caamano, J. & Hunter, C.A. Suppression of NF-κB activation by infection with Toxoplasma gondii. J. Infect. Dis. 185 (Suppl.) 66–72 (2002).

    Article  Google Scholar 

  51. Dobbin, A., Smith, N.C. & Jonson, A.M. Heat shock protein 70 is a potential virulence factor in murine Toxoplasma infection via immunomodulation of host NF-κB and nitric oxide. J. Immunol. 169, 958–965 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Neyer, L.E. et al. Role of interleukin-10 in regulation of T-cell-dependent and T-cell- independent mechanisms of resistance to Toxoplasma gondii. Infect. Immun. 65, 1675–1682 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gazzinelli, R.T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).

    CAS  PubMed  Google Scholar 

  54. Omer, F.M., Kurtzhals, J.A. & Riley, E.M. Maintaining the immunological balance in parasitic infections: a role for TGF-β? Parasitol. Today 16, 18–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Kane, M.M. & Mosser, D.M. The role of IL-10 in promoting disease progression in Leishmaniasis. J. Immunol. 166, 1141–1147 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Barral, A. et al. Transforming growth factor β as a virulence mechanism for Leishmania braziliensis. Proc. Natl. Acad. Sci. USA 90, 3442–3446 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Luder, C.G., Gross, U. & Lopes, M.F. Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions. Trends Parasitol. 17, 480–486 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Moore, K.J., Turco, S.J. & Matlashewski, G. Leishmania donovani infection enhances macrophage viability in the absence of exogenous growth factor. J. Leukoc. Biol. 55, 91–98 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Nash, P.B. et al. Toxoplasma gondii-infected cells are resistant to multiple inducers of apoptosis. J. Immunol. 160, 1824–1830 (1998).

    CAS  PubMed  Google Scholar 

  60. Freire-de-Lima, C.G. et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403, 199–203 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. von Stebut, E., Belkaid, Y., Jakob, T., Sacks, D.L. & Udey, M.C. Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity. J. Exp. Med. 188, 1547–1552 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Marovich, M.A., McDowell, M.A., Thomas, E.K. & Nutman, T.B. IL-12p70 production by Leishmania major-harboring human dendritic cells is a CD40/CD40 ligand-dependent process. J. Immunol. 164, 5858–5865 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Gorak, P.M., Engwerda, C.R. & Kaye, P.M. Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection. Eur. J. Immunol. 28, 687–695 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Subauste, C.S. & Wessendarp, M. Human dendritic cells discriminate between viable and killed Toxoplasma gondii tachyzoites: dendritic cell activation after infection with viable parasites results in CD28 and CD40 ligand signaling that controls IL-12-dependent and -independent T cell production of IFN-γ. J. Immunol. 165, 1498–505 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Scanga, C.A. et al. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J. Immunol. 168, 5997–6001 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Urban, B.C. & Roberts, D.J. Malaria, monocytes, macrophages and myeloid dendritic cells: sticking of infected erythrocytes switches off host cells. Curr. Opin. Immunol. 14, 458–465 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Urban, B.C. et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Urban, B.C., Willcox, N. & Roberts, D.J. A role for CD36 in the regulation of dendritic cell function. Proc. Natl. Acad. Sci. USA 98, 8750–8755 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Newbold, C. et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 57, 389–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Rogerson, S.J. et al. Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria. Am. J. Trop. Med. Hyg. 61, 467–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Van Overtvelt, L. et al. Trypanosoma cruzi infects human dendritic cells and prevents their maturation: inhibition of cytokines, HLA-DR, and costimulatory molecules. Infect. Immun. 67, 4033–4040 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Brodskyn, C. et al. Glycoinositolphospholipids from Trypanosoma cruzi interfere with macrophages and dendritic cell responses. Infect. Immun. 70, 3736–3743 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jebbari, H., Stagg, A.J., Davidson, R.N. & Knight, S.C. Leishmania major promastigotes inhibit dendritic cell motility in vitro. Infect. Immun. 70, 1023–1026 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ponte-Sucre, A., Heise, D. & Moll, H. Leishmania major lipophosphoglycan modulates the phenotype and inhibits migration of murine Langerhans cells. Immunology 104, 462–467 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Konecny, P. et al. Murine dendritic cells internalize Leishmania major promastigotes, produce IL-12 p40 and stimulate primary T cell proliferation in vitro. Eur. J. Immunol. 29, 1803–1811 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Qi, H., Popov, V. & Soong, L. Leishmania amazonensis-dendritic cell interactions in vitro and the priming of parasite-specific CD4+ T cells in vivo. J. Immunol. 167, 4534–4542 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Bennett, C.L., Misslitz, A., Colledge, L., Aebischer, T. & Blackburn, C.C. Silent infection of bone marrow-derived dendritic cells by Leishmania mexicana amastigotes. Eur. J. Immunol. 31, 876–883 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. McDowell, M.A., Marovich, M., Lira, R., Braun, M. & Sacks, D. Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p70 secretion is strain and species dependent. Infect. Immun. 70, 3994–4001 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Turco, S.J., Spath, G.F. & Beverley, S.M. Is lipophosphoglycan a virulence factor? A surprising diversity between Leishmania species. Trends Parasitol. 17, 223–226 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Reis e Sousa, C. et al. Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology. Immunity 11, 637–647 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C.N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature Immunol. 3, 76–82 (2002).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA

    David Sacks & Alan Sher

Authors
  1. David Sacks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Sher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Sacks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sacks, D., Sher, A. Evasion of innate immunity by parasitic protozoa. Nat Immunol 3, 1041–1047 (2002). https://doi.org/10.1038/ni1102-1041

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1102-1041

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