TGF-b2 drives catalase transcription to regulate tumor H2O2 levels, and Theileria gene expression in transformed macrophages

Theileria annulata infects bovine leukocytes causing a lymphoproliferative disease called tropical theileriosis. TGF-b2 is expressed in many tumors and in Theileria-transformed macrophages, but expression diminishes in attenuated macrophages that are used as live vaccines against tropical theileriosis. We show that TGF-b2 drives expression of catalase to reduce the amount of H2O2 produced by both human A549 and HT-29 tumor cell lines and Theileria-transformed bovine macrophages. Attenuated Theileria-transformed macrophages regain a virulent matrigel traversal phenotype when stimulated with TGF-b2, or catalase that reduce H2O2 output. Heightened oxidative stress of attenuated macrophages led to a general down-regulation of parasite genes transcription, a phenomenon reminiscent of artemisinin-induced dormancy of malaria-infected erythrocytes. Reducing infected macrophage stress by TGF-b2, or N-acetylcysteine (NAC) treatments led to a regain in parasite gene transcription and the virulent matrigel traversal phenotype of previously attenuated macrophages. Global downregulation in parasite gene transcription is accompanied by changes in the parasite's chromatin landscape consistent with epigenetic silencing of Theileria encoded host cell tumor virulence traits.