Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances IL-12 responses

Infect Immun. 2014 Jul 14. pii: IAI.01615-14. [Epub ahead of print]

 

Morgado P¹, Sudarshana DM¹, Gov L¹, Harker KS¹, Lam T², Casali P², Boyle JP³, Lodoen MB¹.

 

Toxoplasma gondii is an obligate intracellular parasite that can cause severe neurological disease in infected humans. CD40 is a receptor on macrophages that plays a critical role in controlling T. gondii infection. We examined the regulation of CD40 on the surface of T. gondii-infected bone marrow-derived macrophages (BMdM). T. gondii induced CD40 expression at both the transcript level and on the cell surface, and interestingly, the effect was parasite strain-specific: CD40 levels were dramatically increased in type II T. gondii-infected BMdM compared to type I- or type III-infected cells. Type II induction of CD40 was specific to cells harboring intracellular parasites and detectable as early as 6 hours post-infection (hpi) at the transcript level. CD40 protein expression peaked at 18 hpi. Using forward genetics with progeny from a type II x type III cross, we found that CD40 induction mapped to a region of chromosome X that included the gene encoding the dense granule protein 15 (GRA15). Using type I parasites stably expressing the type II allele of GRA15 (GRA15_II), we found that GRA15_II induced the expression of CD40 on infected cells in an NF-κB-dependent manner. In addition, stable expression of HA-tagged GRA15_II in THP-1 cells resulted in CD40 up-regulation in the absence of infection. Since CD40 signaling contributes to IL-12 production, we examined IL-12 from infected macrophages and found that CD40L engagement of CD40 amplified the IL-12 response in type II-infected cells. These data indicate that GRA15_II induction of CD40 promotes parasite immunity through the production of IL-12.
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PMID:

25024369

[PubMed - as supplied by publisher]