Nipah Virus Impairs Autocrine IFN Signaling by Sequestering STAT1 and STAT2 into Inclusion Bodies

Abstract

Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes fatal infections in humans. As with most disease-causing viruses, the pathogenic potential of NiV is linked to its ability to block antiviral responses, e.g., by antagonizing IFN signaling through blocking STAT proteins. One of the STAT1/2-binding proteins of NiV is the phosphoprotein (P), but its functional role in IFN antagonism in a full viral context is not well defined. As NiV P is required for genome replication and specifically accumulates in cytosolic inclusion bodies (IBs) of infected cells, we hypothesized that this compartmentalization might play a role in P-mediated IFN antagonism. Supporting this notion, we show here that NiV can inhibit IFN-dependent antiviral signaling via a NiV P-dependent sequestration of STAT1 and STAT2 into viral IBs. Consequently, the phosphorylation/activation and nuclear translocation of STAT proteins in response to IFN is limited, as indicated by the lack of nuclear pSTAT in NiV-infected cells. Blocking autocrine IFN signaling by sequestering STAT proteins in IBs is a not yet described mechanism by which NiV could block antiviral gene expression and provides the first evidence that cytosolic NiV IBs may play a functional role in IFN antagonism.

Integrated Computational Biophysics approach for Drug Discovery against Nipah Virus

“…NiV glycoprotein G (NiV-G) has a globular head domain formed of a six-bladed beta-sheet propeller connected via a flexible stalk domain to a transmembrane anchor [10]. The binding of G glycoprotein to its ephrin receptors leads to conformational changes in this glycoprotein, followed by subsequent conformational changes in F glycoprotein that facilitate the fusion of viral and cellular membranes [11,12]. Furthermore, NiV-G/F glycoprotein complexes expressed on infected cell surfaces also facilitate cell-to-cell fusion with neighboring non-infected cells, promoting the spread of infection [13].…”

Integrated Computational Biophysics approach for Drug Discovery against Nipah Virus

“…NiV glycoprotein G (NiV-G) has a globular head domain formed of a six-bladed beta-sheet propeller connected via a flexible stalk domain to a transmembrane anchor [10]. The binding of G glycoprotein to its ephrin receptors leads to conformational changes in this glycoprotein, followed by subsequent conformational changes in F glycoprotein that facilitate the fusion of viral and cellular membranes [11,12]. Furthermore, NiV-G/F glycoprotein complexes expressed on infected cell surfaces also facilitate cell-to-cell fusion with neighboring non-infected cells, promoting the spread of infection [13].…”

Host Cell–Virus Interaction 2.0: Viral Stratagems of Immune Evasion, Host Cellular Responses and Antiviral Counterattacks

“…As obligate intracellular parasites, the exploitation of the target cell for its own survival is of utmost necessity, and one of the ways in which it does so is by fighting against the host defense system. Our first article in the issue unveils a mechanism by which the Nipah virus disrupts the autocrine Interferon (IFN) signaling in the infected cells, emphasizing even more the role of inclusion bodies in Nipah infections, a study reported by Becker and Maisner [ 1 ].…”