Pathogen-associated molecular patterns, such as viral dsRNA replication intermediates, activate expression of interferon-stimulated genes (ISGs). We generated mice transgenic for a picornaviral RNA-dependent RNA polymerase (RdRp^tg mice; the RdRp is from Theiler’s murine encephalomyocarditis virus). RdRp^tg mice have elevated tissue levels of dsRNAs (the RdRp templates on host cell RNAs), and the result is constitutive activation of the MDA5/MAVS pathway, which results in markedly elevated, lifelong expression of a broad panel of ISGs in multiple organs, including brain, spinal cord, liver, lung, heart, and kidney. It is a pure MDA5 activation state in the sense that the other main RIG-I-like receptor, RIG-I, is not involved. The ISG upregulations are completely abrogated by MDA5 (or MAVS) gene (Ifih1) knockout. RIG-I gene KO has no effect. This MDA5 pathway confinement mirrors the MDA5-confined response to replicating picornaviruses. The mice are profoundly resistant to diverse RNA and DNA viruses (EMVC, pseudorabies virus, vesicular stomatitis virus, Friend retrovirus, Theiler virus itself). However, in marked contrast to other human and murine chronic MDA5 activation states, RdRp^tg mice are healthy, with normal longevity and a lack of detectable autoimmune or autoinflammatory diseases. To determine whether the distinctive innate immune system of RdRp^tg mice is transferable post-developmentally by hematopoietic elements, we carried out serum transfers, parabiosis, and bone marrow transplantation (BMT). Intravenous serum transfers did not cause ISG upregulation, but parabiosis of RdRp^tg mice to wild-type mice conferred stable upregulation of ISGs in liver but not brain. BMT conferred increased ISG expression in both liver and brain. BMT also transferred robust resistance to a normally lethal challenge with encephalomyocarditis virus. Thus, cellular elements in blood and bone marrow confer a characteristic RdRp^tg mouse innate immune system reconfiguration with nervous system actualization requiring BMT.