Theileria annulata Hijacks Host Signaling: Integrated Phosphoproteomics and Transcriptomics Unveils ERK1/2 as a Central Regulator of Host Transcription Factors.

Theileria-transformed bovine leukocytes exhibit cancer-like characteristics, but the molecular mechanisms driving these transformations remain unclear. This study provides the first comprehensive phosphoproteomic analysis of both host and parasite in Theileria annulata-infected leukocyte cell lines. We show that T. annulata significantly induces changes in the host protein phosphorylation, impacting key cancer-related processes such as apoptosis suppression, CAMK signaling, and telomere maintenance. A pivotal finding is the parasite's manipulation of the MAPK pathway via sustained ERK1/2 activation, which regulates the phosphorylation of critical transcription factors like RUNX3, FOSL2, BCL6, c-JUN, JUNB, and c-MYC. Transcriptomic analysis of genes controlled by these transcription factors confirmed their role in T. annulata replication. ERK inhibition disrupts phosphorylation, deactivates these transcription factors, and induces apoptosis in infected cells. This underscores the ERK-AP-1 axis as a central mechanism of Theileria pathogenesis and a promising therapeutic target. Additionally, parasite-specific phosphoproteins and kinases were identified, offering new insights into therapeutic strategies to combat infection.