The Roles of a Conserved and Charged Amino Acid Sequence on Enterovirus 3d Polymerase in Viral Infection and Pathogenesis

Enterovirus 71 (EV71) and other enteroviruses are concerning pathogens worldwide. In addition, the increasing number of emerging or reemerging highly pathogenic enteroviral infections, such as EV-D68, indicates the urgency of developing broad-spectrum antivirals against enteroviral infections. One strategy is to identify a highly conserved region that is critical to most enteroviruses. Our group previously identified a nuclear localization signal (NLS) sequence spanning amino acids 126–129 of EV71 3D polymerase (3Dpol) (Figure 1). This NLS sequence, referred to as KK(K/R)D and comprising a continual series of positively charged amino acids, namely lysine (K) or arginine (R) connected to an aspartic acid (D), is highly conserved among enteroviruses (Table 1). Our results obtained by studying a KK(K/R)D-mutant virus demonstrate the relevance of this sequence to EV71 infection and pathogenesis. The goal of the study described in this grant proposal is to further understand the mechanism through which the KK(K/R)D sequence influences enteroviral infections. Specifically, we intend to elucidate the activities and interacting host mechanisms of EV71 3Dpol that are specific to the KK(K/R)D sequence (Aim 1). In addition, we will examine the typical effect of the KK(K/R)D sequence in infections with other enteroviruses, including coxsackievirus B and EV-D68 (Aim 2). Finally, we will evaluate the efficacy of an attenuated vaccine derived from KK(K/R)D-mutant enteroviruses (Aim 3). This research will not only identify a novel factor in viral pathogenicity but also yield new ideas for generating vaccine strains with low pathogenicity and identifying potential broad-spectrum antiviral targets for use against various enteroviral infections.

Project ID:PC10507-0100
External Project ID:MOST105-2320-B182-003