Importance of retinoic acid-inducible gene I and of receptor for type I interferon for cellular resistance to infection by Newcastle disease virus

Abstract

Abstract. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic properties which shows promising effects in the treatment of cancer. Anti-cancer effects are due to the virus ability: i) to replicate in and kill tumor cells, leading finally to their selective elimination; and ii) to induce the stimulation of antitumor activities in immune cells. NDV does not harm normal cells and has a high safety profile. In this study, we first report a direct correlation between the degree of cell resistance to NDV infection and the cellular expression of the retinoic acid-inducible gene I (RIG-I) which is a cytosolic viral RNA receptor. RIG-I plays an important role in the recognition of and response to infection by RNA viruses. We also demonstrate that impairment of the interferon (IFN) pathway through deletion of the receptor for type I IFN (IFNR1) in primary macrophages leads to NDV replication. In tumor cells, addition of exogenous IFN-α4 is shown to lead to tumor growth reduction and inhibition of viral replication. Finally, increase of the RIG-I concentration of tumor cells via plasmid transfection is shown to be associated with a stronger resistance to NDV infection. These findings shed new light on the crucial role played by the cytosolic receptor RIG-I and the plasma membrane receptor IFNR1 as key molecules to protect cells against infection by NDV.

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“…In normal cells of non-permissive hosts (rodents, humans), signaling via RIG-I (intracellular recognition of viral RNA) and amplification via an IFN induced feedback loop by membrane-expressed type I IFN receptor (IFNRA) [61] leads to an effective interferon response, induction of anti-viral gene expression and prevention of NDV replication. NDV and NDV-induced IFNα is involved in polarization of DCs towards DC1, a genetic programming process that only takes 18 h and involves 24 transcription factors leading to upregulation of 779 genes [62].…”

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“…NDV induces in human PBMC, DCs and monocytes a strong type I IFN response [4,6,15,40]. This occurs within 18–24 h and consists of an early phase and a late phase.…”

“…The studies revealed an important role in the IFN response of RIG-I, IRF3, IFN-β and IRF7 [6,27]. In addition, studies with cells from Knock-out mice devoid of the gene for IFNRA showed the importance of this receptor: In its absence, normal cells were incapable of preventing NDV replication [49,50].…”

“…The recognition of 5′-triphosphate (non-capped) viral leader RNA in the cytoplasm of NDV infected human cells by retinoic-acid-inducible gene I (RIG-I) [5] initiates a strong type I interferon (IFN) response [6] and is a good example of RNA–protein interaction. Another example is a recently identified host cell-derived microRNA which targets RIG-I mRNA for degradation [7].…”

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“…Complete cellular resistance to NDV infection has been demonstrated in mammalian cells lacking specific sialylated moieties (mainly gangliosides, and N-syalilated glycoproteins) on the cell surface (absence of receptors) [20], while increased tolerance to NDV-induced cell death in cell culture has been associated with the presence of specific intracellular pathogen sensors – such as Retinoic Acid-Inducible Gene I (RIG-I) [21, 22]; increased type-I interferon response [23, 24]; and activity of the Mx protein family [25–27]. Also viral interference, although not a cellular resistance per se , inhibits NDV superinfection [28–30].…”