Abstract
Theileria-infected macrophages display many features of cancer cells such as heightened invasive capacity; however, the tumor-like phenotype is reversible by killing the parasite. Moreover, virulent macrophages can be attenuated by multiple in vitro passages and so provide a powerful model to elucidate mechanisms related to transformed macrophage virulence. Here, we demonstrate that in two independent Theileria-transformed macrophage cell lines Grb2 expression is down-regulated concomitant with loss of tumor virulence. Using peptidimer-c to ablate SH2 and SH3 interactions of Grb2 we identify TGF-receptor II and the p85 subunit of PI3-K, as Grb2 partners in virulent macrophages. Ablation of Grb2 interactions reduces PI3-K recruitment to TGF-RII and decreases PIP3 production, and dampens JNK phosphorylation and AP-1-driven transcriptional activity down to levels characteristic of attenuated macrophages. Loss of TGF-R>PI3-K>JNK>AP-1 signaling negatively impacts on virulence traits such as reduced JAM-L/ITG4A and Fos-B/MMP9 expression that contribute to virulent macrophage adhesion and invasiveness.
Highlights
In regions endemic for tropical theileriosis indigenous breeds of cattle are more resistant to disease, exhibit less symptoms and recover from an infectious dose, which is often fatal to non-indigenous breeds[6]
We have previously shown that Theileria-infected Ode macrophages that display a heightened capacity of adhesion typical of virulent disease-causing infected macrophages compared to live vaccine lines used to treat tropical theileriosis that are attenuated for this virulence trait[30]
Taken together; the results show that Transforming growth factor-β (TGF-β) 2-signaling is responsible for high levels of Grb[2] in virulent Theileria-infected macrophages of different geographical origins and ablation of Grb[2] accompanies loss of Theileria-transformed macrophage virulence
Summary
In regions endemic for tropical theileriosis indigenous breeds of cattle (ex: Bos indicus known as Sahiwals) are more resistant to disease, exhibit less symptoms and recover from an infectious dose, which is often fatal to non-indigenous breeds (ex: B. taurus known as Holstein-Friesian—HF)[6]. PI3-kinases are capable of phosphorylating the 3-position hydroxyl group of the inositol ring of phosphatidylinositol to form phosphatidylinositol biphosphate (PIP2) and phosphatidylinositol triphosphate (PIP3) and other 3-phosphorylated phosphoinositides This group of signaling kinases contains phosphoinositide-binding domains that are recruited for binding to cell membranes. Both we, and others have previously demonstrated that T. parva and T. annulata-infected B-lymphocytes rely on constitutively activated PI3-K for their continued proliferation[8,19,20]. Proteins of the Jun and Fos families combine to form the heterodimeric AP-1 transcription factor, which enters the nucleus and binds to specific DNA sequences to modulate target gene expression. AP-1 is a key transcription factor induced in virulent Theileria-transformed leukocytes[23] and AP-1-driven transcription underpins the hyper-dissemination virulence phenotype[25]
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