Differential Induction of TLR3-Dependent Innate Immune Signaling by Closely Related Parasite Species

<div><p>The closely related protozoan parasites <i>Toxoplasma gondii</i> and <i>Neospora caninum</i> display similar life cycles, subcellular ultrastructure, invasion mechanisms, metabolic pathways, and genome organization, but differ in their host range and disease pathogenesis. Type II (γ) interferon has long been known to be the major mediator of innate and adaptive immunity to <i>Toxoplasma</i> infection, but genome-wide expression profiling of infected host cells indicates that <i>Neospora</i> is a potent activator of the type I (α/β) interferon pathways typically associated with antiviral responses. Infection of macrophages from mice with targeted deletions in various innate sensing genes demonstrates that host responses to <i>Neospora</i> are dependent on the toll-like receptor <i>Tlr3</i> and the adapter protein <i>Trif</i>. Consistent with this observation, RNA from <i>Neospora</i> elicits TLR3-dependent type I interferon responses when targeted to the host endo-lysosomal system. Although live <i>Toxoplasma</i> fail to induce type I interferon, heat-killed parasites do trigger this response, albeit much weaker than <i>Neospora</i>, and co-infection studies reveal that <i>T. gondii</i> actively suppresses the production of type I interferon. These findings reveal that eukaryotic pathogens can be potent inducers of type I interferon and that related parasite species interact with this pathway in distinct ways.</p>