Molecular insights of immune evasion by Orf Virus: the interaction and functional impact of viral OH1 phosphatase on STAT1.

Orf virus, a member of the Parapoxvirus genus within the Poxvirus family, is the causative agent of Contagious Ecthyma, a zoonotic infection primarily affecting goats and sheep. The immune response against Orf virus is short-lived, enabling the virus to repeatedly infect animals, regardless of their vaccination status. Several virulence factors, including the OH1 tyrosine phosphatase, are responsible for the modulation of the host immune response. Here, we report the direct interaction between the viral OH1 and the human transcription factor STAT1 identified as a physiological OH1 substrate. Indeed, our results demonstrate that OH1 dephosphorylates STAT1 at pTyr701, resulting in a subsequent impairing of its nuclear import. By employing protein-protein docking and molecular dynamics simulations, we modelled the STAT1-OH1 complex, phosphorylated or not, and dissected the structural basis of its mutual recognition. Also, we identified additional potential substrates of OH1 that show to be involved in cell trafficking, thereby expanding our understanding of the host-triggered immune responses elicited by Poxviruses. Overall, this study provides insights into the molecular mechanisms underlying immune evasion in Orf virus, extending our knowledge towards new therapeutic strategies against this pathogen.