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Poeschla laboratory reports new transgenic model of stably augmented innate immunity in PLoS Pathogens


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. 

      In Painter et al., (PLoS Pathogens, published Dec. 3, 2015), the authors studied a virus in the Picornaviridae, which contains diverse viruses that cause diseases that range from poliomyelitis to the Enterovirus D68 paralysis recently encountered here in Denver, to the common cold. (More generally, it is a member of the positive-strand RNA viruses, which is the largest family of viruses and contains many human pathogens, such as Dengue, Chikungunya, Norovirus, West Nile, SARS, Rubella, Hepatitis C, Yellow Fever, Rhinoviruses, and others). 
 
     The results show that transgenic expression of the viral RNA-dependent RNA polymerase (the RdRP, which is the genome-replicating enzyme), in the absence of the numerous other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally tightly 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 challenges by diverse RNA and DNA viruses. Multiple genetic crosses with mice knocked out for key immune system genes (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive (antibody- and cytotoxic T cell-generating) immune system. Two 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 signals within the RdRP mRNA. Rather, it operates at the protein level and it requires RdRP catalysis. Importantly and intriguingly, despite lifelong massive ISG elevations, the RdRP mice are entirely healthy, with normal longevity. 
 
     This study opens a new area of investigation and triggers a bounty of testable questions. It reveals that a powerfully augmented MDA5-mediated activation state can be a well-tolerated, stable mammalian innate immune system configuration. It suggests translational possibilities for augmenting innate immunity to achieve broad-spectrum antiviral protection. The  lack of autoimmune (or any) disease, which contrasts with previously studied mouse and rare human constitutive MDA5 activation states and other “interferonopathies,” has potential to aid understanding of the triggering and maintenance of autoimmune diseases. The authors are immensely grateful for funding from the John H. Tietze Foundation, a legacy of a grateful patient and a wise man.