title: Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection.
abstract: Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-kappaB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.
authors.affiliation: Gadi Research Centre, Division of Science and Design, University of Canberra, Canberra, ACT 2601, Australia. Lidbury@scides.canberra.edu.au
authors.forename: B A
authors.initials: BA
authors.lastname: Lidbury
authors.forename: S
authors.initials: S
authors.lastname: Mahalingam
mesh_terms: D018354:Alphavirus Infections / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D019067:Antibody-Dependent Enhancement; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000378:metabolism; D012398:Ross River virus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014709:Vero Cells; D010948:Viral Plaque Assay
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010750:Phosphoproteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse