Processing of Genome 5′ Termini as a Strategy of Negative-Strand RNA Viruses to Avoid RIG-I-Dependent Interferon Induction

Abstract

Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5′ triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5′ triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5′ monophosphate-specific exonuclease indicates that the RIG-I-activating 5′ triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5′ end as a strategy of viruses to evade the innate immune response.

Reversal of hepatitis B virus-induced immune tolerance by an immunostimulatory 3p-HBx-siRNAs in a retinoic acid inducible gene I–dependent manner

“…Moreover, this therapeutic strategy can be extended to other viral diseases, especially for positiveand negative-strand RNA viruses (e.g., influenza virus, rabies virus, or hepatitis C virus), which are recognized by RIG-I. 13,14,19,22 It is not certain whether immune cells, such as Kupffer cells, hepatic DC cells, and even liver sinusoid endothelial cells, in addition to hepatocytes within the liver, might either take up siRNAs or respond to immune stimulations induced by siRNA, then activate to recruit other immune cells into the liver to mount an adaptive immune response. It should also be noticed that inducing potent type I IFN responses that can activate a wide range of innate and adaptive immune cells would potentially have serious adverse effects, particularly if the therapy is administered systemically.…”

“…13,14 Although 3p-siRNAs were described to induce type I IFN in several cell types, [15][16][17] other synthetic RIG-I agonists lacking 5 0 -triphosphate, such as polyinosinicpolycytidylic acid (poly [I:C]), 18,19 and some natural RNAs, such as viral transcripts, 13-15 also serve as RIG-I agonists. So, RIG-I activation leads to the production of type I IFNs and inflammatory cytokines, which play an important role in inhibiting HBV replication via reversing HBV-induced tolerance.…”

Paramyxovirus evasion of innate immunity: Diverse strategies for common targets

“…TLRs are trans-membrane proteins expressed at the plasma membrane or on intracellular structures such as endosomes and the endoplasmic reticulum [37,38] to detect extracellular viral nucleic acids such as dsRNA (TLR3) [37][38][39][40] and G/U-rich ssRNAs (TLR7) [38] . By contrast, the almost ubiquitously expressed RLR helicases RIG-Ⅰ and MDA5 detect viral dsRNA in the cytoplasm of infected cells [36,[41][42][43][44][45][46][47] ; RIG-Ⅰ also recognises cytoplasmic 5' tri-phosphorylated and uncapped viral ssRNA [48][49][50] . RNA-activated MDA5 and RIG-Ⅰ interact with the mitochondrial membraneassociated adaptor protein IFNβ promoter stimulator 1 (IPS-1, also known as MAVS, VISA, or CARDIF) via their caspase activation and recruitment domains (CARDs) to trigger downstream signalling ( Figure 3).…”

Epidemiology and host spectrum of Borna disease virus infections

“…Polymerase activity is important in the adaptation of BDV to new hosts (Ackermann et al, 2007) and the X protein regulates viral polymerase activity and inhibits apoptosis, being essential for host survival (Poenisch et al, 2009). BDV uniquely limits its genome amplification by trimming the genome, which may favour non-cytolytic virus persistence and evasion of the antiviral host response (Habjan et al, 2008;Schneider et al, 2005). BDV infection produces an extremely low number of infectious virus particles per cell, although the cells express high BDV RNA and protein levels ; reviewed by Tomonaga et al, 2002).…”

“…In infected laboratory rats, BDV has several pharmacological effects in the brain, and studies have revealed additional mechanisms by which BDV interacts with host cells, impairs neuronal functions and affects innate immunity (Habjan et al, 2008;Prat et al, 2009;Qian et al, 2010;Solbrig, 2010;Weissenböck et al, 2000). Adult immunocompetent rats succumb to severe meningoencephalitis, whereas neonatally infected or immunocompromised rats and bank voles cope with BDV despite widespread virus, high antigen amount, subtle symptoms and occasional mild inflammatory reactions (Table 2; reviewed by Pletnikov et al, 2002).…”