Maladaptation after a virus host switch leads to increased activation of the pro-inflammatory NF-κB pathway

SignificanceMyxoma virus (MYXV) is benign in the natural brush rabbit host but causes a fatal disease in European rabbits. Here, we demonstrate that MYXV M156 inhibited brush rabbit protein kinase R (bPKR) more efficiently than European rabbit PKR (ePKR). Because ePKR was not completely inhibited by M156, there was a depletion of short-half-life proteins like the nuclear factor kappa B (NF-κB) inhibitor IκBα, concomitant NF-κB activation and NF-κB target protein expression in ePKR-expressing cells. NF-κB pathway activation was blocked by either hypoactive or hyperactive M156 mutants. This demonstrates that maladaptation of viral immune antagonists can result in substantially different immune responses in aberrant hosts. These different host responses may contribute to altered viral dissemination and may influence viral pathogenesis.