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.
Alexander
J
J
Department of Immunology, University of Strathclyde, Glasgow, UK.
Scharton-Kersten
T M
TM
Yap
G
G
Roberts
C W
CW
Liew
F Y
FY
Sher
A
A
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D014122:Toxoplasma / Q000254:growth & development* / Q000472:pathogenicity*; D014123:Toxoplasmosis / Q000378:metabolism* / Q000469:parasitology*
D016207:Cytokines; D009569:Nitric Oxide