Mechanisms of innate resistance toToxoplasma gondiiinfection

Abstract

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 immunocompetent 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-de¢cient mice have demonstrated the interleukin-12 (IL-12)-dependent production of interferon (IFN-) to be of paramount importance in controlling early parasite growth. However, this seems to be independent of nitric oxide production as mice de¢cient 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 e¡ector pathways against this parasite distinct from that described for macrophages. Once initiated, IL-12-dependent IFN-production in synergy with other proin£ammatory cytokines can positively feed back on itself to induce`cytokine shock'. Regulatory cytokines, particularly IL-10, are essential to down-regulate in£ammation and limit host pathology.

Inhibition of caspase activation and a requirement for NF-κB function in theToxoplasma gondii-mediated blockade of host apoptosis

“…Accordingly, Wei et al (Wei et al, 2002) have demonstrated that T.-gondii-infected dendritic cells are resistant to apoptosis but trigger a contactdependent apoptosis in cytotoxic T cells. Modulation of the balance between apoptosis and necrosis at a site of tissue infection could modulate the inflammatory response, thereby promoting either growth as a tachyzoite or triggering stage conversion to the long-term bradyzoite form associated with chronic infection (Alexander et al, 1997;Yap and Sher, 1999). This conversion is crucial for the long-term survival of T. gondii within the host as it mounts an effective immune response against it (Alexander et al, 1997;Yap and Sher, 1999).…”

“…Modulation of the balance between apoptosis and necrosis at a site of tissue infection could modulate the inflammatory response, thereby promoting either growth as a tachyzoite or triggering stage conversion to the long-term bradyzoite form associated with chronic infection (Alexander et al, 1997;Yap and Sher, 1999). This conversion is crucial for the long-term survival of T. gondii within the host as it mounts an effective immune response against it (Alexander et al, 1997;Yap and Sher, 1999). Bradyzoites possess considerably lowered metabolic activity and persist for long periods of time (years to decades), with their intracellular localization affording them protection from immune attack (Dubey, 1998;Dubey et al, 1998).…”

Toxoplasma gondiiTachyzoites Inhibit Proinflammatory Cytokine Induction in Infected Macrophages by Preventing Nuclear Translocation of the Transcription Factor NF-κB

“…The latter are essential to control infection (11)(12)(13). The tachyzoite form of the parasite invades a variety of cells, where it resides within a specialized parasitophorous vacuole that is created during initial parasite entry into the host cell.…”

Microarray Analysis Reveals Previously Unknown Changes in Toxoplasma gondii-infected Human Cells

“…tion, primarily via dendritic cell activation (6,8,9). However, the mechanism by which infected cells activate and recruit dendritic cells remain unclear but presumably requires synthesis of C-C chemokines that bind and activate the C-C chemokine receptor, CCR5 (10).…”