Conservation of a Unique Mechanism of Immune Evasion across the Lyssavirus Genus

Abstract

The evasion of host innate immunity by Rabies virus, the prototype of the genus Lyssavirus, depends on a unique mechanism of selective targeting of interferon-activated STAT proteins by the viral phosphoprotein (P-protein). However, the immune evasion strategies of other lyssaviruses, including several lethal human pathogens, are unresolved. Here, we show that this mechanism is conserved between the most distantly related members of the genus, providing important insights into the pathogenesis and potential therapeutic targeting of lyssaviruses.

Identification of a Role for Nucleolin in Rabies Virus Infection

“…At 18 h posttransfection, cells were lysed, and immunoprecipitation (IP) of GFP-fused proteins was performed using the GFP-trap system (ChromoTek) (8). Lysates (input) and IPs were analyzed by immunoblotting (IB) using antibodies against NCL or GFP.…”

“…The RABV phosphoprotein (P-protein) has critical roles in genome transcription/replication and antagonism of interferon (IFN)-dependent antiviral responses (2)(3)(4)(5)(6)(7)(8)(9). In infected cells, the P gene produces full-length P-protein (P1) and several N-terminally truncated isoforms, predominantly P2 and P3, via a ribosomal leaky scanning mechanism (7,10).…”

The Rabies Virus Interferon Antagonist P Protein Interacts with Activated STAT3 and Inhibits Gp130 Receptor Signaling

“…Because of their pivotal roles in antiviral innate immunity, STAT1 and -2 are among the principal targets of IFN antagonists (2,3), including the lyssavirus phosphoproteins (P proteins) (see below), paramyxovirus V proteins, and dengue virus NS5 protein, which interact physically with STAT1 and/or -2 to inhibit their activity (4)(5)(6)(7)(8). However, it is well known that IFN-␣/␤ signaling also activates other members of the STAT family, including STAT3 (which is activated by phosphorylation at residue Y705), resulting in the generation of alternative STAT complexes that modify the IFN-activated transcriptional signature (1).…”

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

“…The STATs can be bound by all isoforms by a site in the conserved P protein CTD (Wiltzer et al, 2012), enabling cytoplasmic P1, as well as presumably P2, and microtubuleassociated P3 to effect their exclusion from the nucleus Brzozka et al, 2005;Moseley et al, 2009;Vidy et al, 2005;Wiltzer et al, 2012). P1 also binds and inhibits STAT3 nuclear translocation in response to the IL6 family cytokine oncostatin M Oksayan et al, 2012a).…”

“…Notably, several key trafficking sequences show broad conservation in the lyssavirus genus, indicative of important roles in viral biology (Jacob et al, 2000;Pasdeloup et al, 2005;Wiltzer et al, 2012). RABV P protein contains two nuclear trafficking modules/domains, located in the N-terminal region (NTR) (Oksayan et al, 2012b) and globular CTD (Pasdeloup et al, 2005;Rowe et al, 2016), both of which incorporate a CRM1-dependent NES and an IMPbinding NLS in overlapping or closely associated sequences, enabling efficient co-regulation of import and export.…”