Wilkins, C, Dishongh, R, Moore, SC, Whitt, MA, Chow, M and Machaca, K. RNA interference is an antiviral defence mechanism in Caenorhabditis elegans. Nature 436: 1044-1047

Department of Microbiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Nature (Impact Factor: 41.46). 09/2005; 436(7053):1044-7. DOI: 10.1038/nature03957
Source: PubMed


RNA interference (RNAi) is an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism that is well defined genetically in Caenorhabditis elegans. RNAi has been postulated to function as an adaptive antiviral immune mechanism in the worm, but there is no experimental evidence for this. Part of the limitation is that there are no known natural viral pathogens of C. elegans. Here we describe an infection model in C. elegans using the mammalian pathogen vesicular stomatitis virus (VSV) to study the role of RNAi in antiviral immunity. VSV infection is potentiated in cells derived from RNAi-defective worm mutants (rde-1; rde-4), leading to the production of infectious progeny virus, and is inhibited in mutants with an enhanced RNAi response (rrf-3; eri-1). Because the RNAi response occurs in the absence of exogenously added VSV small interfering RNAs, these results show that RNAi is activated during VSV infection and that RNAi is a genuine antiviral immune defence mechanism in the worm.

Download full-text


Available from: Michael A Whitt
  • Source
    • "For instance, HIV-1 shows higher replication capacity in cells that have suffered knockout of Dicer and Drosha expression [30]. In this sense, the mammalian stomatitis virus achieved increased accumulation in Caenorhabditis elegans with defective RNAi machinery [31]. It has been also observed that the interferon (IFN) pathway works in coordination with miRNA to control viral infections. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The efforts made to develop RNAi-based therapies have led to productive research in the field of infections in humans, such as hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), herpetic keratitis, human papillomavirus, or influenza virus. Naked RNAi molecules are rapidly digested by nucleases in the serum, and due to their negative surface charge, entry into the cell cytoplasm is also hampered, which makes necessary the use of delivery systems to exploit the full potential of RNAi therapeutics. Lipid nanoparticles (LNP) represent one of the most widely used delivery systems for in vivo application of RNAi due to their relative safety and simplicity of production, joint with the enhanced payload and protection of encapsulated RNAs. Moreover, LNP may be functionalized to reach target cells, and they may be used to combine RNAi molecules with conventional drug substances to reduce resistance or improve efficiency. This review features the current application of LNP in RNAi mediated therapy against viral infections and aims to explore possible future lines of action in this field.
    Full-text · Article · Aug 2014 · BioMed Research International
  • Source
    • "Given the importance of this question, we sought to formally evaluate the mammalian response to virus to determine whether RNAi is a physiological contributor to this process. To this end, we generated two virus model systems using a vaccine strain of VSV that is exquisitely sensitive to both IFN and RNAi (Mueller et al., 2010; Vogel and Fertsch, 1987; Wilkins et al., 2005). For this, we inserted the only known mammalian virus protein capable of degrading small RNAs loaded into a RISC (VACV VP55) or a RIG-I antagonist of IAV (IAV NS1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A successful cellular response to virus infection is essential for evolutionary survival. In plants, arthropods, and nematodes, cellular antiviral defenses rely on RNAi. Interestingly, the mammalian response to virus is predominantly orchestrated through interferon (IFN)-mediated induction of antiviral proteins. Despite the potency of the IFN system, it remains unclear whether mammals also have the capacity to employ antiviral RNAi. Here, we investigated this by disabling IFN function, small RNA function, or both activities in the context of virus infection. We find that loss of small RNAs in the context of an in vivo RNA virus infection lowers titers due to reduced transcriptional repression of the host antiviral response. In contrast, enabling a virus with the capacity to inhibit the IFN system results in increased titers. Taken together, these results indicate that small RNA silencing is not a physiological contributor to the IFN-mediated cellular response to virus infection.
    Full-text · Article · Jun 2014 · Cell Reports
  • Source
    • "In C. elegans, endogenous viral pathogens were unknown until recently [65] [66]. Therefore, the antiviral role of RNAi was studied by infecting with C. elegans under laboratory conditions with viruses having a broad host range such as the (+)ssRNA flock house virus (FHV) [67] or the (À)ssRNA vesicular stomatitis virus (VSV) [68] [69]. Infection with the 4 P. Svoboda / FEBS Letters xxx (2014) xxx–xxx Please cite this article in press as: Svoboda, P. Renaissance of mammalian endogenous RNAi. "
    [Show abstract] [Hide abstract]
    ABSTRACT: RNA interference (RNAi) denotes sequence-specific mRNA degradation induced by long double-stranded RNA (dsRNA). RNAi is an ancient eukaryotic defense mechanism against viruses and mobile elements. In mammals, endogenous RNAi was outstripped during evolution by the current innate and acquired immunity. The RNAi apparatus, which remains essentially intact, serves mostly the microRNA pathway, which regulates endogenous gene expression. Remarkably, several recent publications brought the mammalian endogenous RNAi pathway back into the spotlight. Here, I will provide an up-to-date review of the mammalian endogenous RNAi pathway with a focus on its defensive role and overlaps with miRNA and piRNA pathways.
    Full-text · Article · May 2014 · FEBS Letters
Show more