The Relevance of Nuclear Entry of Enterovirus RNA-Dependent RNA Polymerase to Viral Infection and Viral Pathogenicity

EV71 and other enteroviruses are concerning pathogens for countries worldwide. An increasing number of emerging or reemerging highly pathogenic enterovirus infections (e.g., EV-D68) also emphasize the urgency to develop broad-spectrum antivirals against pan-enterovirus infections. One strategy is to identify a highly conserved region that is critical to most of the enteroviruses. Our group previously identified a nuclear localization signal (NLS) sequence spanning amino acids 126 to 129 of the EV71 3Dpol that is responsible for transporting the 3Dpol into the nucleus of infected cells (Figure 1). This NLS sequence, which is composed of continuous positively charged amino acids, namely lysinine (K) or arginine (R) connected to an aspartic acid (D), is highly conserved among enteroviruses (Table 1). However, the relevance of the 3Dpol nuclear entry to enterovirus infection has not yet been addressed. The goal of this proposal is to evaluate the role of 3Dpol nuclear entry (NLS activity) to viral replication and pathogenesis. Our preliminary results in the study of NLS-mutated viruses suggested the critical function of NLS sequences in EV71 infection (Figure 2). This grant proposal outlines a study to elucidate the role of viral 3Dpol nuclear entry in viral replication and pathogenicity by using NLS-mutated viruses (Aims 1 and 2) and by using nuclear-transporting blockers (Aim 3) in enterovirus-infected cells and mice. This research will not only identify a novel factor in viral pathogenicity but also yield new ideas for generating low pathogenic vaccine strains and identifying potential broad-spectrum antiviral targets to be used against various enterovirus infections.

Project ID:PC10404-0016
External Project ID:MOST104-2320-B182-004