• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of transbhomepageaboutsubmitalertseditorial board
Philos Trans R Soc Lond B Biol Sci. Sep 29, 1997; 352(1359): 1355–1359.
PMCID: PMC1692026

Mechanisms of innate resistance to Toxoplasma gondii infection.


The interaction of protozoan parasites with innate host defences is critical in determining the character of the subsequent infection. The initial steps in the encounter of Toxoplasma gondii with the vertebrate immune system provide a striking example of this important aspect of the host-parasite relationship. In immuno-competent individuals this intracellular protozoan produces an asymptomatic chronic infection as part of its strategy for transmission. Nevertheless, T. gondii is inherently a highly virulent pathogen. The rapid induction by the parasite of a potent cell-mediated immune response that both limits its growth and drives conversion to a dormant cyst stage explains this apparent paradox. Studies with gene-deficient mice have demonstrated the interleukin-12 (IL-12)-dependent production of interferon gamma (IFN-gamma) to be of paramount importance in controlling early parasite growth. However, this seems to be independent of nitric oxide production as mice deficient in inducible nitric oxide synthase (iNOS) and tumour necrosis factor receptor were able to control early growth of T. gondii, although, they later succumbed to infection. Nitric oxide does, however, seem to be important in controlling persistent infection; treating chronic infection with iNOS metabolic inhibitors results in disease reactivation. Preliminary evidence implicates neutrophils in effector pathways against this parasite distinct from that described for macrophages. Once initiated, IL-12-dependent IFN-gamma production in synergy with other proinflammatory cytokines can positively feed back on itself to induce 'cytokine shock'. Regulatory cytokines, particularly IL-10, are essential to down-regulate inflammation and limit host pathology.

Full Text

The Full Text of this article is available as a PDF (109K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alexander J, Jebbari H, Bluethmann H, Satoskar A, Roberts CW. Immunological control of Toxoplasma gondii and appropriate vaccine design. Curr Top Microbiol Immunol. 1996;219:183–195. [PubMed]
  • Ambroise-Thomas P, Pelloux H. Toxoplasmosis - congenital and in immunocompromised patients: a parallel. Parasitol Today. 1993 Feb;9(2):61–63. [PubMed]
  • Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1. J Immunol. 1995 Aug 1;155(3):1066–1073. [PubMed]
  • Bohne W, Heesemann J, Gross U. Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion. Infect Immun. 1994 May;62(5):1761–1767. [PMC free article] [PubMed]
  • Candolfi E, Hunter CA, Remington JS. Mitogen- and antigen-specific proliferation of T cells in murine toxoplasmosis is inhibited by reactive nitrogen intermediates. Infect Immun. 1994 May;62(5):1995–2001. [PMC free article] [PubMed]
  • Chao CC, Anderson WR, Hu S, Gekker G, Martella A, Peterson PK. Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism. Clin Immunol Immunopathol. 1993 May;67(2):178–183. [PubMed]
  • Clark IA, Rockett KA, Cowden WB. Proposed link between cytokines, nitric oxide and human cerebral malaria. Parasitol Today. 1991 Aug;7(8):205–207. [PubMed]
  • D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. [PMC free article] [PubMed]
  • Däubener W, Remscheid C, Nockemann S, Pilz K, Seghrouchni S, Mackenzie C, Hadding U. Anti-parasitic effector mechanisms in human brain tumor cells: role of interferon-gamma and tumor necrosis factor-alpha. Eur J Immunol. 1996 Feb;26(2):487–492. [PubMed]
  • Neyer LE, Grunig G, Fort M, Remington JS, Rennick D, Hunter CA. Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii. Infect Immun. 1997 May;65(5):1675–1682. [PMC free article] [PubMed]
  • Flesch IE, Hess JH, Huang S, Aguet M, Rothe J, Bluethmann H, Kaufmann SH. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J Exp Med. 1995 May 1;181(5):1615–1621. [PMC free article] [PubMed]
  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed]
  • Gazzinelli R, Xu Y, Hieny S, Cheever A, Sher A. Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. J Immunol. 1992 Jul 1;149(1):175–180. [PubMed]
  • Gazzinelli RT, Hieny S, Wynn TA, Wolf S, Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. [PMC free article] [PubMed]
  • Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed]
  • Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kühn R, Müller W, Trinchieri G, Sher A. 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-gamma and TNF-alpha. J Immunol. 1996 Jul 15;157(2):798–805. [PubMed]
  • Hauser WE, Jr, Sharma SD, Remington JS. Natural killer cells induced by acute and chronic toxoplasma infection. Cell Immunol. 1982 May 15;69(2):330–346. [PubMed]
  • Hayashi S, Chan CC, Gazzinelli R, Roberge FG. Contribution of nitric oxide to the host parasite equilibrium in toxoplasmosis. J Immunol. 1996 Feb 15;156(4):1476–1481. [PubMed]
  • Hunter CA, Abrams JS, Beaman MH, Remington JS. Cytokine mRNA in the central nervous system of SCID mice infected with Toxoplasma gondii: importance of T-cell-independent regulation of resistance to T. gondii. Infect Immun. 1993 Oct;61(10):4038–4044. [PMC free article] [PubMed]
  • Hunter CA, Litton MJ, Remington JS, Abrams JS. Immunocytochemical detection of cytokines in the lymph nodes and brains of mice resistant or susceptible to toxoplasmic encephalitis. J Infect Dis. 1994 Oct;170(4):939–945. [PubMed]
  • Hunter CA, Chizzonite R, Remington JS. IL-1 beta is required for IL-12 to induce production of IFN-gamma by NK cells. A role for IL-1 beta in the T cell-independent mechanism of resistance against intracellular pathogens. J Immunol. 1995 Nov 1;155(9):4347–4354. [PubMed]
  • Hunter CA, Bermudez L, Beernink H, Waegell W, Remington JS. Transforming growth factor-beta inhibits interleukin-12-induced production of interferon-gamma by natural killer cells: a role for transforming growth factor-beta in the regulation of T cell-independent resistance to Toxoplasma gondii. Eur J Immunol. 1995 Apr;25(4):994–1000. [PubMed]
  • Jackson SH, Gallin JI, Holland SM. The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med. 1995 Sep 1;182(3):751–758. [PMC free article] [PubMed]
  • Johnson LL. SCID mouse models of acute and relapsing chronic Toxoplasma gondii infections. Infect Immun. 1992 Sep;60(9):3719–3724. [PMC free article] [PubMed]
  • Jun CD, Kim SH, Soh CT, Kang SS, Chung HT. Nitric oxide mediates the toxoplasmastatic activity of murine microglial cells in vitro. Immunol Invest. 1993 Dec;22(8):487–501. [PubMed]
  • Khan IA, Matsuura T, Kasper LH. IL-10 mediates immunosuppression following primary infection with Toxoplasma gondii in mice. Parasite Immunol. 1995 Apr;17(4):185–195. [PubMed]
  • Khan IA, Matsuura T, Fonseka S, Kasper LH. Production of nitric oxide (NO) is not essential for protection against acute Toxoplasma gondii infection in IRF-1-/- mice. J Immunol. 1996 Jan 15;156(2):636–643. [PubMed]
  • Langermans JA, Van der Hulst ME, Nibbering PH, Hiemstra PS, Fransen L, Van Furth R. IFN-gamma-induced L-arginine-dependent toxoplasmastatic activity in murine peritoneal macrophages is mediated by endogenous tumor necrosis factor-alpha. J Immunol. 1992 Jan 15;148(2):568–574. [PubMed]
  • Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis. 1992 Aug;15(2):211–222. [PubMed]
  • McCabe RE, Luft BJ, Remington JS. Effect of murine interferon gamma on murine toxoplasmosis. J Infect Dis. 1984 Dec;150(6):961–962. [PubMed]
  • Murray HW, Cohn ZA. Macrophage oxygen-dependent antimicrobial activity. I. Susceptibility of Toxoplasma gondii to oxygen intermediates. J Exp Med. 1979 Oct 1;150(4):938–949. [PMC free article] [PubMed]
  • Murray HW, Juangbhanich CW, Nathan CF, Cohn ZA. Macrophage oxygen-dependent antimicrobial activity. II. The role of oxygen intermediates. J Exp Med. 1979 Oct 1;150(4):950–964. [PMC free article] [PubMed]
  • Murray HW, Szuro-Sudol A, Wellner D, Oca MJ, Granger AM, Libby DM, Rothermel CD, Rubin BY. Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages. Infect Immun. 1989 Mar;57(3):845–849. [PMC free article] [PubMed]
  • Pfefferkorn ER, Eckel M, Rebhun S. Interferon-gamma suppresses the growth of Toxoplasma gondii in human fibroblasts through starvation for tryptophan. Mol Biochem Parasitol. 1986 Sep;20(3):215–224. [PubMed]
  • Rennick D, Berg D, Holland G. Interleukin 10: an overview. Prog Growth Factor Res. 1992;4(3):207–227. [PubMed]
  • Roberts CW, Satoskar A, Alexander J. Sex steroids, pregnancy-associated hormones and immunity to parasitic infection. Parasitol Today. 1996 Oct;12(10):382–388. [PubMed]
  • Rogers HW, Unanue ER. Neutrophils are involved in acute, nonspecific resistance to Listeria monocytogenes in mice. Infect Immun. 1993 Dec;61(12):5090–5096. [PMC free article] [PubMed]
  • Romani L, Mencacci A, Cenci E, Spaccapelo R, Toniatti C, Puccetti P, Bistoni F, Poli V. Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans. J Exp Med. 1996 Apr 1;183(4):1345–1355. [PMC free article] [PubMed]
  • Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hieny S, Gazzinelli RT, Sher A. In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J Immunol. 1996 Nov 1;157(9):4045–4054. [PubMed]
  • Scharton-Kersten TM, Yap G, Magram J, Sher A. Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med. 1997 Apr 7;185(7):1261–1273. [PMC free article] [PubMed]
  • Schlüter D, Deckert-Schlüter M, Schwendemann G, Brunner H, Hof H. Expression of major histocompatibility complex class II antigens and levels of interferon-gamma, tumour necrosis factor, and interleukin-6 in cerebrospinal fluid and serum in Toxoplasma gondii-infected SCID and immunocompetent C.B-17 mice. Immunology. 1993 Mar;78(3):430–435. [PMC free article] [PubMed]
  • Schwartzman JD, Gonias SL, Pfefferkorn ER. Murine gamma interferon fails to inhibit Toxoplasma gondii growth in murine fibroblasts. Infect Immun. 1990 Mar;58(3):833–834. [PMC free article] [PubMed]
  • Sher A, Oswald IP, Hieny S, Gazzinelli RT. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha. J Immunol. 1993 May 1;150(9):3982–3989. [PubMed]
  • Suzuki Y, Orellana MA, Schreiber RD, Remington JS. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. [PubMed]
  • Suzuki Y, Conley FK, Remington JS. Importance of endogenous IFN-gamma for prevention of toxoplasmic encephalitis in mice. J Immunol. 1989 Sep 15;143(6):2045–2050. [PubMed]
  • Suzuki Y, Conley FK, Remington JS. Treatment of toxoplasmic encephalitis in mice with recombinant gamma interferon. Infect Immun. 1990 Sep;58(9):3050–3055. [PMC free article] [PubMed]
  • Suzuki Y, Yang Q, Yang S, Nguyen N, Lim S, Liesenfeld O, Kojima T, Remington JS. IL-4 is protective against development of toxoplasmic encephalitis. J Immunol. 1996 Sep 15;157(6):2564–2569. [PubMed]
  • Wilson CB, Remington JS. Activity of human blood leukocytes against Toxoplasma gondii. J Infect Dis. 1979 Dec;140(6):890–895. [PubMed]
  • Yong EC, Chi EY, Fritsche TR, Henderson WR., Jr Human platelet-mediated cytotoxicity against Toxoplasma gondii: role of thromboxane. J Exp Med. 1991 Jan 1;173(1):65–78. [PMC free article] [PubMed]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...