The ability of enveloped negative strand RNA viruses of the family Paramyxoviridae to rapidly disseminate throughout a broad range of host species is often a cause of fatal diseases. The threat to humans and animals posed by these viruses is well illustrated by recent outbreaks of fatal encephalitis in southeast Asia and Australia resulting from the previously unrecognized Paramyxoviruses, Nipah virus and Hendra virus. Within the Paramyxoviridae, many criteria have distinguished Nipah and Hendra viruses as representative of a new genus, Henipavirus. One genomic feature that positively links them to other paramyxoviruses is a conserved cysteine-rich protein domain that is the hallmark of paramyxovirus 'V' proteins. The V proteins of other paramyxoviruses have been linked to evasion of host interferon (IFN) signal transduction and subsequent innate antiviral responses, by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Preliminary investigations demonstrate that the Nipah virus V protein evades host IFN-activated defenses by a different mechanism. Nipah virus V protein does not induce STAT protein degradation, but instead induces formation of high molectflar weight cytoplasmic complexes that contain STAT1 and STAT2. Thus, Nipah virus V protein expression alters STAT subcellular distribution in the steady-state, prevents IFNstimulated STAT tyrosine phosphorylation, and blocks IFN-induced STAT nuclear relocalization, resulting in inhibition of cellular responses to either IFNalpha/beta or IFNgamma. The V protein is situated at the paramyxovirus-host interface and is not only a potential pathogenesis-determining factor, but also represents a therapeutic target for pharmaceutical intervention and vaccine development, contributing to an armamentarium for the control of natural outbreaks or bioterrorist threats. The molecular basis for Henipavirus V protein anti-cellular functions will be investigated with three aims to: (i) Determine the ability of Hendra virus V protein to prevent STAT function in WN signal transduction (ii) Define critical functional domains involved in Henipavirus IFN evasion and subcellular distribution, and (iii) Characterize components and assemble of V protein-induced IFN evasion complexes.
| Ludlow, Louise E; Lo, Michael K; Rodriguez, Jason J et al. (2008) Henipavirus V protein association with Polo-like kinase reveals functional overlap with STAT1 binding and interferon evasion. J Virol 82:6259-71 |
| Rodriguez, Jason J; Cruz, Cristian D; Horvath, Curt M (2004) Identification of the nuclear export signal and STAT-binding domains of the Nipah virus V protein reveals mechanisms underlying interferon evasion. J Virol 78:5358-67 |
| Rodriguez, Jason J; Horvath, Curt M (2004) Host evasion by emerging paramyxoviruses: Hendra virus and Nipah virus v proteins inhibit interferon signaling. Viral Immunol 17:210-9 |
| Horvath, Curt M (2004) Weapons of STAT destruction. Interferon evasion by paramyxovirus V protein. Eur J Biochem 271:4621-8 |
