title: Toxoplasma gondii rhoptry 16 kinase promotes host resistance to oral infection and intestinal inflammation only in the context of the dense granule protein GRA15.
abstract: Toxoplasma gondii transmission between intermediate hosts is dependent on the ingestion of walled cysts formed during the chronic phase of infection. Immediately following consumption, the parasite must ensure survival of the host by preventing adverse inflammatory responses and/or by limiting its own replication. Since the Toxoplasma secreted effectors rhoptry 16 kinase (ROP16) and dense granule 15 (GRA15) activate the JAK-STAT3/6 and NF-κB signaling pathways, respectively, we explored whether a particular combination of these effectors impacted intestinal inflammation and parasite survival in vivo. Here we report that expression of the STAT-activating version of ROP16 in the type II strain (strain II+ROP16I) promotes host resistance to oral infection only in the context of endogenous GRA15 expression. Protection was characterized by a lower intestinal parasite burden and dampened inflammation. Host resistance to the II+ROP16I strain occurred independently of STAT6 and the T cell coinhibitory receptors B7-DC and B7-H1, two receptors that are upregulated by ROP16. In addition, coexpression of ROP16 and GRA15 enhanced parasite susceptibility within tumor necrosis factor alpha/gamma interferon-stimulated macrophages in a STAT3/6-independent manner. Transcriptional profiling of infected STAT3- and STAT6-deficient macrophages and parasitized Peyer's patches from mice orally challenged with strain II+ROP16I suggested that ROP16 activated STAT5 to modulate host gene expression. Consistent with this supposition, the ROP16 kinase induced the sustained phosphorylation and nuclear localization of STAT5 in Toxoplasma-infected cells. In summary, only the combined expression of both GRA15 and ROP16 promoted host resistance to acute oral infection, and Toxoplasma may possibly target the STAT5 signaling pathway to generate protective immunity in the gut.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Kirk D C
authors.initials: KD
authors.lastname: Jensen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hu
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Whitmarsh
authors.forename: Musa A
authors.initials: MA
authors.lastname: Hassan
authors.forename: Lindsay
authors.initials: L
authors.lastname: Julien
authors.forename: Diana
authors.initials: D
authors.lastname: Lu
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000473:pathology*; D007422:Intestines / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000469:parasitology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014122:Toxoplasma / Q000201:enzymology*; D014124:Toxoplasmosis, Animal / Q000469:parasitology* / Q000473:pathology
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D015800:Protozoan Proteins; D011505:Protein-Tyrosine Kinases; C552524:Rop16 protein, Toxoplasma gondii
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