The reovirus σ3 protein inhibits NF-κB-dependent antiviral signaling

Abstract

Viral antagonism of innate immune pathways is a common mechanism by which viruses evade immune surveillance. Infection of host cells with reovirus leads to the blockade of NF-{kappa}B, a key transcriptional regulator of the hosts innate immune response. One mechanism by which reovirus infection results in inhibition of NF-{kappa}B is through a diminishment in levels of upstream activators, IKK{beta} and NEMO. Here, we demonstrate a second, distinct mechanism by which reovirus blocks NF-{kappa}B. We report that expression of a single viral protein, {sigma}3, is sufficient to inhibit expression of NF-{kappa}B target genes. Further, {sigma}3-mediated blockade of NF-{kappa}B occurs without changes to IKK levels or activity. Expression of only a subset of NF-{kappa}B target genes is reduced. Among NF-{kappa}B targets, the expression of type I interferon is significantly diminished by {sigma}3 expression. Correspondingly, ectopic expression of {sigma}3 enhances viral replication. Expression of NF-{kappa}B target genes varies following infection with closely related reovirus strains. Our genetic analysis identifies that these differences are controlled by polymorphisms in the amino acid sequence of {sigma}3. This work identifies a new role for reovirus {sigma}3 as a viral antagonist of the NF-{kappa}B-dependent antiviral pathways. IMPORTANCEHost cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected cells. The NF-{kappa}B family of proteins is important for the cell to mediate this response. In this study, we show that a single protein, {sigma}3, produced by mammalian reovirus, impairs the function of NF-{kappa}B. We demonstrate that by blocking NF-{kappa}B, {sigma}3 diminishes the hosts response to infection and promotes viral replication. This work identifies a second, previously unknown mechanism by which reovirus blocks this aspect of the host cell response.