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

Pedro Morgado, Dattanand M. Sudarshana, Lanny Gov, Katherine S. Harker, Tonika Lam, Paolo Casali, Jon P. Boyle, Melissa B. Lodoen

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 (BMdMs). T. gondii induced CD40 expression both at 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 BMdMs 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 h postinfection (hpi) at the transcript level. CD40 protein expression peaked at 18 hpi. Using forward genetics with progeny from a type II×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 (GRA15II), we found that type I GRA15II parasites induced the expression of CD40 on infected cells in an NF-κB-dependent manner. In addition, stable expression of hemagglutinin-tagged GRA15II in THP-1 cells resulted in CD40 upregulation in the absence of infection. Since CD40 signaling contributes to interleukin-12 (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 GRA15II induction of CD40 promotes parasite immunity through the production of IL-12.

Original languageEnglish (US)
Pages (from-to)4047-4055
Number of pages9
JournalInfection and Immunity
Volume82
Issue number10
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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    Morgado, P., Sudarshana, D. M., Gov, L., Harker, K. S., Lam, T., Casali, P., Boyle, J. P., & Lodoen, M. B. (2014). Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances interleukin-12 responses. Infection and Immunity, 82(10), 4047-4055. https://doi.org/10.1128/IAI.01615-14