Interferon signaling antagonism by Marburg virus and its role in host tropism

Marburgvirus (MARV) and Ebolavirus (EBOV), members of the Filoviridae family, are causative agents of lethal hemorrhagic fever in primates, but unable to cause lethal disease in adult mice unless adapted to these species. Disease progression in fatal cases correlates with perturbed host innate and adaptive immune responses. Filoviruses antagonize the production and the effects of interferon (IFN), a critical component of innate immunity. VP24 of Zaire Ebolavirus (ZEBOV) inhibits the nuclear accumulation of activated STAT1 and the subsequent activation of IFN stimulated genes (ISGs) by binding to karyopherin alpha1, the nuclear localization signal receptor for STAT1. VP24s from ZEBOV, Reston Ebolavirus (REBOV) and mouse adapted Ebolavirus (MA-EBOV), bind to karyopherin alpha1, alpha5 and alpha6 (NPI-1 subfamily) and disrupt their interaction with phospho-STAT1 in human and mouse cells. Infection of IFN-treated human cells revealed that STAT1 phosphorylation was inhibited by MARV but not EBOV. Surprisingly, the MARV matrix protein VP40 antagonizes the antiviral effects of IFN through the inhibition of Jak1 phosphorylation. The effect is specific on Jak1 and not Tyk2, resembling the phenotype observed in Jak1 null cells. Interestingly, the IFN antagonist function of VP40 is independent of its function as a matrix protein. VP40 from Ravn strain (RAVV-a distinct Marburgvirus clade) also blocks IFN dependent signaling in human cells. However, neither MARV nor RAVV VP40 was able to do so in IFN treated murine cells. VP40 from the mouse-adapted strain of RAVV was able to inhibit Jak1 and STAT phosphorylation as well as to counteract the antiviral effects of IFN in mouse cells. Finally, the identity of 2 amino acid residues (V57 and T165) is crucial for VP40's ability to antagonize IFN signaling in murine cells.;To conclude, we show that EBOV VP24's ability to interfere with the interaction between karyopherins of the NPI-1 family and phospho-STAT1 is conserved among different EBOV species, we point out a novel function of the MARV matrix protein VP40 and a difference in the biology and ability between the two filovirus genera to evade immune responses, and finally we highlight the role of IFN antagonism and define specific genetic determinants of host range and virulence.