Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance

Abstract

Viral infection induces production of type I interferons (IFNs), which stimulate the expression of a variety of antiviral factors to inhibit viral replication. To establish effective infection, viruses need to develop strategies to evade the immune responses. A neurovirulent Sindbis virus strain with neuroinvasive properties (SVNI) causes lethal encephalitis in mice, and its replication in cultured cells is inhibited by the zinc finger antiviral protein (ZAP), a host factor that specifically inhibits the replication of certain viruses by binding to the viral mRNAs, repressing the translation of target mRNA, and promoting the degradation of target mRNA. We report here that murine embryonic fibroblast cells from ZAP knockout mice supported more efficient SVNI replication than wild-type cells. SVNI infection of 10-day-old suckling mice led to reduced survival in the knockout mice. Unexpectedly, however, SVNI infection of 23-day-old weanling mice, whose immune system is more developed than that of the suckling mice, resulted in significantly improved survival in ZAP knockout mice. Further analyses revealed that in the weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of IFN production, which restricted viral spread to the central nervous system. Blocking IFN activity through the use of receptor-neutralizing antibodies rendered knockout mice more sensitive to SVNI infection than wild-type mice. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance. IMPORTANCESindbis virus, a prototypic member of the Alphavirus genus, has been used to study the pathogenesis of acute viral encephalitis in mice for many years. How the virus evades immune surveillance to establish effective infection is largely unknown. ZAP is a host antiviral factor that potently inhibits Sindbis virus replication in cell culture. We show here that infection of ZAP knockout suckling mice with an SVNI led to faster disease progression. However, SVNI infection of weanling mice led to slower disease progression in knockout mice. Further analyses revealed that in weanling knockout mice, SVNI replicated more efficiently in lymphoid tissues at early times postinfection and induced higher levels of interferon production, which restricted viral spread to the central nervous system. These results uncover a mechanism by which SVNI exploits a host antiviral factor to evade innate immune surveillance and allow enhanced neuroinvasion.

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1

“…We first used mouse embryonic fibroblasts (MEFs) isolated from wild-type and ZAP knockout mice to evaluate the antiviral activity of endogenous ZAP. In the knockout cells, the second exon, which encodes a fragment of the N-terminal domain of ZAP protein, was deleted, so that neither the ZAPS nor the ZAPL protein could be expressed (30). The basal mRNA levels of ZAPS and ZAPL were relatively low in wild-type MEFs, and IAV infection upregulated their expression (Fig.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…In vivo, Zap knockout (Zc3hav1 −/− ) mice showed enhanced replication of SINV in 10-d-old mice as expected (Kozaki et al 2015). Though surprisingly, in 23-d-old weanling pups it was shown that a neurovirulent strain of SINV can use ZAP to decrease its replication in initially infected cells in vivo such that it prevents immune recognition, allowing the virus to spread to the central nervous system (CNS) and promote disease (Wang et al 2016).…”

Regulation of HIV-1 Gag-Pol Expression by Shiftless, an Inhibitor of Programmed -1 Ribosomal Frameshifting

“…The production and titration of replication-competent Sindbis virus SINV-nluc have been previously described (Wang et al, 2016b). To prepare the virus, the infectious clone SINV-nsP3-nluc was linearized with XhoI and in vitro transcribed into RNA with SP6 RNA polymerase (Promega) in the presence of a Cap analog (Promega).…”