The Toxoplasma gondii virulence factor ROP16 acts in cis and trans, and suppresses T cell responses
Longfei Chen1,2, David A Christian2, Joshua A Kochanowsky3
1Department of Pathogen Biology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
Abstract:
The ability of Toxoplasma gondii to inject the rhoptry kinase ROP16 into host cells results in the activation of the transcription factors STAT3 and STAT6, but it is unclear how these events impact infection. Here, parasites that inject Cre-recombinase with rhoptry proteins were used to distinguish infected macrophages from those only injected with parasite proteins. Transcriptional profiling revealed that injection of rhoptry proteins alone was sufficient to induce an M2 phenotype that is dependent on STAT3 and STAT6, but only infected cells displayed reduced expression of genes associated with antimicrobial activity and protective immunity. In vivo, the absence of STAT3 or STAT6 improved parasite control, while the loss of ROP16 resulted in a marked reduction in parasite numbers and heightened parasite-specific T cell responses. Thus, ROP16 is a virulence factor that can act in cis and trans to promote M2 programs and which limits the magnitude of parasite-specific T cell responses.
Insights
Toxoplasma gondii
Area of Science:
- Immunology
- Molecular Biology
- Parasitology
Background:
- Toxoplasma gondii injects rhoptry kinase ROP16 into host cells, activating STAT3 and STAT6.
- The precise impact of ROP16-mediated STAT activation on infection remains unclear.
Purpose of the Study:
- To elucidate the role of ROP16 and STAT3/STAT6 in T. gondii infection.
- To differentiate the effects of rhoptry protein injection from cellular infection.
Main Methods:
- Utilized genetically modified parasites expressing Cre-recombinase with rhoptry proteins.
- Employed transcriptional profiling to analyze host cell responses.
- Conducted in vivo studies to assess parasite control and T cell responses.
Main Results:
- Rhoptry protein injection alone induced an M2 macrophage phenotype dependent on STAT3 and STAT6.
- Only infected cells showed reduced expression of antimicrobial and immune genes.
- STAT3 or STAT6 deficiency improved parasite control in vivo.
- ROP16 deficiency significantly reduced parasite numbers and enhanced T cell responses.
Conclusions:
- ROP16 acts as a virulence factor, promoting M2 polarization via STAT3/STAT6.
- ROP16 limits the magnitude of parasite-specific T cell responses.
- Targeting ROP16 may be a strategy for controlling toxoplasmosis.
