Abstract
The closely related protozoan parasites Toxoplasma gondii and Neospora caninum 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 Toxoplasma infection, but genome-wide expression profiling of infected host cells indicates that Neospora 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 Neospora are dependent on the toll-like receptor Tlr3 and the adapter protein Trif. Consistent with this observation, RNA from Neospora elicits TLR3-dependent type I interferon responses when targeted to the host endo-lysosomal system. Although live Toxoplasma fail to induce type I interferon, heat-killed parasites do trigger this response, albeit much weaker than Neospora, and co-infection studies reveal that T. gondii 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.
Highlights
The eukaryotic phylum apicomplexa is comprised of over 5000 species of parasitic protozoa that infect a wide range of animal hosts and cause significant disease in both healthy and immunecompromised individuals
In order to compare host transcriptional responses during Neospora and Toxoplasma infection, whole-genome expression profiling was carried out using human fibroblasts infected with either Neospora caninum (NcLiv strain) or Toxoplasma gondii (GT1, Prugniaud, or VEG strains, selected as representatives of the three dominant genotypes observed in North America [22,23]). 822 host genes were identified as differentially transcribed ($2-fold, FDR#5%) during infection with any of these four parasites relative to uninfected host cells (Fig. 1a and Table S1)
Hierarchical clustering of the 822 genes revealed a distinctive set of 66 genes induced only during Neospora infection (Fig. 1a, asterisk; Fig. 1b), and Gene Ontology (GO) analysis [24] indicated that these are significantly associated with antiviral responses (Fig. 1c)
Summary
The eukaryotic phylum apicomplexa is comprised of over 5000 species of parasitic protozoa that infect a wide range of animal hosts and cause significant disease in both healthy and immunecompromised individuals This phylum includes Plasmodium, the causative agent of malaria; Cryptosporidium, recently recognized to be a leading cause of pediatric diarrheal disease in the developing world [1]; and Toxoplasma, a ubiquitous parasite that causes potentially fatal congenital disease and represents the second leading cause of food borne mortality in the USA [2]. The vast majority of studies on innate immunity to protozoan parasites have focused on IFN-c produced during acute infection by NK cells [8,9], and interleukin-12 produced by macrophages [10], neutrophils [11,12] and dendritic cells [13] It is unclear whether this accurately captures the complete picture of innate immune pathways triggered by infection with protozoa. While tremendous progress has been made in identifying viral and bacterial ligands recognized by innate pattern recognition receptors [14], relatively few studies have explored the mechanisms and consequences of innate recognition of intracellular eukaryotic microbes [15], in part because the conserved signatures of bacteria and viruses are not generally thought to be present in eukaryotic cells
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