All positive strand RNA viruses studied to date rearranged cellular membranes to promote their own replication. One reason for these rearrangements is that these viruses replicate their genomic RNA in association with cellular membranes. In poliovirus (PV), a model for a host of medically important positive strand RNA viruses, two distinct classes of vesicle have been identified. One class, a single-membraned vesicle which resembles a COPII secretory transport vesicle, associates with viral RNA replication proteins. The second type of vesicle, which is double-membraned, also associates with viral RNA replication proteins and resembles the autophagosome, an organelle induced by a pathway of cellular homeostasis and stress-response known as autophagy. Autophagosome-like vesicles are specifically induced by viruses and promote PV production. The long term goal of this project is to understand the mechanisms and consequences of cellular membrane rearrangements by picornaviruses. The objective of this application is to identify the roles played by autophagosomes during infection and define the mechanism by which PV induces autophagosome morphogenesis. Our preliminary data indicate that autophagy is required for optimal levels of infectious virus. Autophagic signaling is required for viral RNA replication. However, vesicle acidification, which in the case of autophagosomes is required for fusion with lysosomes, is required for cleavage of a viral capsid protein, the final step in generating infectious virus from newly formed virions. The central hypothesis of this proposal is that PV infection generates autophagosomes through morphological changes, including invagination, in the PIP4-rich secretory pathway-derived vesicles used for RNA replication. Acidification of the newly formed autophagosomes promotes virion maturation. The central hypothesis will be tested by pursuing two specific aims.
In Aim I we will study the nature of the vesicle environment, and the requirements for virion maturation.
In Aim II we will analyze the development of autophagic vesicles during infection and define the proteome of virus-induced autophagosomes. The rationale for this research is to understand how picornaviruses subvert what is often an anti-pathogen pathway to promote virion maturation. This will provide us with information needed to target this late step in virus production with therapeutics. Our innovative approaches will identify the mechanisms PV uses to induce autophagosomes, and how they promote maturation and egress of infectious virus. The proposed research is significant because it will fundamentally advance our understanding of how a medically important family of viruses subverts a basic cellular pathway to promote virus replication. This work will provide novel insights into the late stages of the viral life cycle, especially maturation and cellular egress, and provide the first steps in identifying therapeutic targets that may ultimately lead to treatments against multiple viral diseases. This work is also an important step in understanding the mechanisms of existing and future therapeutic agents against multiple viral diseases.
Picornaviruses are a major cause of several diverse human diseases, and studies of poliovirus inform our understanding of this viral family. This project wil analyze how poliovirus interacts with its cellular environment, to understand how small acidic compartments within cells can promote the creation of infectious virions. Understanding this process may lead to therapeutics targeting development of acidic compartments during infection, to prevent formation of infectious virus.
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