Grant: Project Grant

Enteroviruses (EVs) are common human pathogens associated with a broad spectrum of diseases, including various neurological disorders, such as poliomyelitis, aseptic meningitis, encephalitis, and non-polio flaccid paralysis, particularly in infants and children worldwide. Autophagy is a "self-eating" process in cells by which cells recycle damaged proteins and/or cell parts, called organelles. Autophagy is an important cellular response to limit viral growth and further infection. However, increasing evidence suggests that this pathway can be "hijacked" by EVs to ensure their successful infection of host cells. We discovered that EV infection disrupts the normal process of autophagy, resulting in enhanced viral replication/release and impaired clearance of damaged proteins that clump together and are toxic to the cells. We further showed that several proteins involved in the regulation of autophagy are broken down upon viral infection through the action of virus-encoded proteins. Despite the demonstrated importance of autophagy in EV infections, the exact mechanism by which EVs subvert this pathway and the functional significance of the resulting protein breakdown remain largely unclear. In addition, the possible value of autophagy-based anti-EV inhibitors has not been studied. In this project, we propose to: (1) investigate the mechanism by which EVs interfere with the process of autophagy; (2) determine the outcome of impaired function of lysosome (an organelle that contains digestive enzymes required for autophagy-mediated recycling); and (3) develop anti-viral inhibitors based on the mechanism identified in cells that prevent EV-mediated disruption of autophagy. These studies will provide new information and advance our understanding regarding the factors that govern successful viral infection and contribute to disease progression. Results generated from these studies also offer a potential to identify new strategies to prevent and treat EV infections.