Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity

Abstract

For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection.

Case-Control Comparison of Enteric Viromes in Captive Rhesus Macaques with Acute or Idiopathic Chronic Diarrhea

“…Pathogenic viruses may also share receptors or intracellular proteins/pathways also required by other viruses, thereby reducing their availability for viral replication. Innate antiviral responses may also be induced by potentially "protective" viruses that increase resistance to high-level replication by pathogenic viruses in the same (sapelovirus versus enterovirus) or different (parvovirus versus enterovirus) viral families (73)(74)(75)(76)(77)(78).…”

Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus

“…Studies since the 1990s have indicated that expression of viral RdRp can activate the immune system and confer resistance to viral infection on plant cells (55)(56)(57). Several research groups have recently reported that expression of viral RdRps can also activate the innate immune system in mammalian cells (28,58,59). The RdRps of hepatitis C virus (HCV), Semliki Forest virus (SFV), and Theiler's murine encephalitis virus (TMEV) produce dsRNAs in transfected cells even in the absence of viral genomic RNA, and these dsRNAs, as pathogen-associated molecular patterns (PAMPs), are recognized by PRRs, which then trigger RLR/MAVS signaling pathway activation and induce IFN-I production.…”

Type I interferon–mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview

“…As an allied but distinct point, the identification of dominant gain-of-function mutations in IFIH1 has highlighted the possibility of clinical nonpenetrance into old age in the presence of life-long, marked overexpression of ISGs (Rice et al, 2014). This situation is reminiscent of a mouse model where transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP) leads to a dramatic up-regulation of ISG stimulation and profound viral resistance via an MDA5/MAVS-dependent pathway, but where the mice are entirely healthy (Painter et al, 2015). The contrast with mouse models also showing type I interferon up-regulation, but demonstrating a clear link between interferon expression and phenotype, might relate to the involvement of other inflammatory cytokines in the latter cases.…”