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Yellow Fever Virus Capsid Protein Is a Potent Suppressor of RNA Silencing That Binds Double-Stranded RNA

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Yellow Fever Virus Capsid Protein Is a Potent Suppressor of RNA Silencing That Binds Double-Stranded RNA Yellow fever virus capsid protein is a potent suppressor of RNA silencing that binds double-stranded RNA Glady Hazitha Samuela, Michael R. Wileyb,1, Atif Badawib, Zach N. Adelmana, and Kevin M. Mylesa,2 aDepartment of Entomology, Texas A&M University, College Station, TX 77843; and bDepartment of Entomology, Fralin Life Science Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 Edited by George Dimopoulos, Johns Hopkins School of Public Health, Baltimore, MD, and accepted by Editorial Board Member Carolina Barillas-Mury October 6, 2016 (received for review January 13, 2016) Mosquito-borne flaviviruses, including yellow fever virus (YFV), Zika intermediates (RIs) produced during viral infection activate an an- virus (ZIKV), and West Nile virus (WNV), profoundly affect human tiviral defense based on RNA silencing (6). In flies, the ribonuclease health. The successful transmission of these viruses to a human host Dicer-2 (Dcr-2) recognizes dsRNA (7). Cleavage of dsRNA RIs by depends on the pathogen’s ability to overcome a potentially sterilizing Dcr-2 generates viral small interfering RNAs (vsiRNAs) ∼21 nt in immune response in the vector mosquito. Similar to other invertebrate length. These siRNA duplexes are incorporated into the RNA- animals and plants, the mosquito’s RNA silencing pathway comprises induced silencing complex (RISC). RISC maturation involves loading its primary antiviral defense. Although a diverse range of plant and a duplex siRNA, choosing and retaining a guide strand, and ejecting insect viruses has been found to encode suppressors of RNA silencing, the antiparallel passenger strand (8–11). The guide strand directs the mechanisms by which flaviviruses antagonize antiviral small RNA Argonaute 2 (Ago-2), an essential RISC component possessing en- pathways in disease vectors are unknown. Here we describe a viral donuclease activity, to complementary RNAs in the cell, leading to suppressor of RNA silencing (VSR) encoded by the prototype flavivirus, their sequence-specific degradation. When infected with RNA YFV. We show that the YFV capsid (YFC) protein inhibits RNA silencing viruses, Drosophila melanogaster dcr-2 or ago-2 loss-of-function mu- in the mosquito Aedes aegypti by interfering with Dicer. This VSR tants exhibit an “enhanced disease phenotype,” characterized by activity appears to be broadly conserved in the C proteins of other elevated levels of virus replication and increased mortality (12–14). medically important flaviviruses, including that of ZIKV. These results In an evolutionary “arms race,” the genomes of numerous plant suggest that a molecular “arms race” between vector and pathogen and insect viruses have evolved to encode one or more viral underlies the continued existence of flaviviruses in nature. suppressors of RNA silencing (VSRs) (15, 16). For example, the flock house virus (FHV) B2 is a well-characterized dsRNA-binding yellow fever virus | flavivirus | capsid | Zika virus | RNA interference protein that shields the RIs produced during viral infection from processing by Dcr-2 and interferes with the incorporation of – rthropod-borne viruses (arboviruses) are maintained in na- vsiRNA duplexes into the RISC (17 20). Well-documented ex- Ature through transmission cycles that involve alternating amples of plant and insect virus proteins that interfere with small replication in hematophageous insect vectors and vertebrate hosts. RNA pathways suggest that arboviruses may encode similar The Flavivirus genus of the family Flaviviridae contains a number of important mosquito-borne viruses responsible for large epidemics Significance of human disease. These include Zika virus (ZIKV), West Nile virus (WNV), dengue virus (DENV; serotypes 1–4), Japanese encepha- Until it was demonstrated that the Aedes aegypti mosquito litis virus (JEV), and the type virus for the family, yellow fever virus transmitted yellow fever, the disease was possibly the most (YFV). The YFV genome is a single-stranded RNA of positive feared pestilence in the western hemisphere. This finding, by MICROBIOLOGY polarity that is ∼11 kb in length. The 5′-capped RNA encodes the Walter Reed’s Yellow Fever Commission, is credited with eradi- structural proteins (C-prM-E) and nonstructural proteins (NS1- cation of the disease in many areas, through sanitation programs NS2A-NS2B-NS3-NS4A-2K-NS4B-NS5) (1). Nonstructural com- designed to eliminate the vector. Since this discovery, the mos- ponents are assembled, with host factors, into membrane-bound quito has been widely believed to be complicit in the transmission replication complexes, where the various enzymatic functions of of viral diseases, earning the enmity of humans everywhere. these proteins (e.g., RNA-dependent RNA polymerase, helicase, However, we show here that yellow fever virus encodes a protein capping machinery) replicate the genome. The relatively smooth that blocks the mosquito’s immune response, suggesting the surface of the flavivirus virion is decorated with the envelope (E) pathogen’s continued existence in nature depends on staying one and membrane (M) proteins, anchored into the host-derived lipid step ahead of the vector’s antiviral defense. bilayer via C-terminal transmembrane domains. Within the virion is a nucleocapsid core comprising a single copy of the RNA genome Author contributions: Z.N.A. and K.M.M. designed research; G.H.S., M.W., and K.M.M. in complex with multiple capsid (C) proteins (2–4).Inanurban performed research; G.H.S., M.W., and A.B. contributed new reagents/analytic tools; G.H.S., M.W., Z.N.A., and K.M.M. analyzed data; and G.H.S., Z.N.A., and K.M.M. wrote transmission cycle, the yellow fever mosquito, Aedes aegypti, ac- the paper. quires the virus after feeding on an infected human host. After a The authors declare no conflict of interest. brief incubation period, the mosquito may transmit the virus to This article is a PNAS Direct Submission. G.D. is a Guest Editor invited by the Editorial other susceptible humans. Although infection of the vertebrate Board. human host is often associated with pathology and disease, a per- Freely available online through the PNAS open access option. sistent nonlethal infection is established in the insect vector. Data deposition: The data reported in this paper have been deposited in the Gene Ex- When vector mosquitoes become infected with arboviral patho- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE80691). gens, antiviral immunity is essential to the survival of the insect (5). 1Present address: Center for Genome Sciences, United States Army Medical Research In- Although a sufficiently robust immune response may be sterilizing, stitute of Infectious Diseases, Fort Detrick, MD 21702. the antiviral defenses of the mosquito are not always an effective 2To whom correspondence should be addressed. Email: [email protected]. barrier to the transmission of viral pathogens. In plant and in- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. vertebrate organisms, double-stranded RNA (dsRNA) replicative 1073/pnas.1600544113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1600544113 PNAS | November 29, 2016 | vol. 113 | no. 48 | 13863–13868 Downloaded by guest on October 2, 2021 proteins; however, the mechanisms by which medically important arboviruses modulate small RNA pathways to productively infect disease vectors remain unknown. Elucidating these mechanisms would fundamentally alter our understanding of pathogen trans- mission by arthropod vectors. We have previously shown that an antiviral response directed by vsiRNAs is essential to limiting the pathogenesis of arbovirus infections in mosquitoes (5). Suppressing the accumulation of vsiRNAs in Ae. aegypti by infection with a recombinant Sindbis virus (SINV) expressing the FHV B2 resulted in elevated levels of virus replication and increased mortality, i.e., a disease phe- notype. In the present study, we show that this phenotype can be used to reliably identify VSRs that interfere with RNA silencing by diverse mechanisms. Thus, to investigate the possible pres- ence of VSRs encoded in the genomes of flaviviruses and other mosquito-borne pathogens, we infected Ae. aegypti with recombi- nant SINVs (Alphavirus genus) expressing heterologous virus se- quences. Here we report suppression of RNA silencing in Ae. aegypti mosquitoes infected with a recombinant SINV expressing the yellow fever virus capsid (YFC). Furthermore, through a series of bio- chemical assays, we demonstrate that the observed antagonism Fig. 1. A disease phenotype in Ae. aegypti infected with recombinant SINVs of RNA silencing is mediated by the binding of YFC to long expressing heterologous VSR proteins. (A) Schematic of a recombinant SINV dsRNAs, interfering with the production of vsiRNAs by Dicer. expressing a VSR from an engineered subgenomic promoter (SG2). (B)Sur- Finally, we provide evidence that this VSR activity is broadly vival of mosquitoes after infection with recombinant SINVs expressing well- conserved in the C proteins of other medically important flavi- known VSR proteins (red triangles) or with viruses containing non- viruses, including that of ZIKV. translatable versions of the VSR sequences (black circles). Survival curves represent cohorts of ≥40 adult female mosquitoes injected with 500 pfu of Results virus. Significance was determined using the Mantel–Cox log-rank test. Studies identifying VSRs have often been guided by previous experimental evidence implicating
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