Receptor Binding And Early Steps Of Cellular Infection By Parvoviruses
Parvoviruses are small, non-enveloped, single stranded DNA viruses. The specific attributes of the capsid and genome dictate how the virus interacts with the environment and the host cell in terms of transmission, tissue tropism, anti-viral immunity, and disease states. A major focus of these studies is viral entry into host cells. During infection, the parvovirus capsid hijacks cellular pathways to reach the nucleus for genome replication. Receptor binding is critical for determining host range and tissue tropism, and various receptors are utilized by different parvoviruses. However, the intracellular trafficking pathways followed by viruses after endocytosis are poorly understood. Chapter 2 examines the dynamic nature of parvoviral uptake and entry by wild type viruses, while chapter 3 examines the ability of these viruses to use variant receptors for uptake and infection. In addition to successfully navigating entry into host cells, parvoviruses must survive in the environment and evade host defenses. Humoral immunity plays a particularly important role in the control of these viruses. This is a benefit as vaccination is generally successful in controlling parvoviral disease, but is a challenge that must be overcome in the development of adeno-associated viruses as gene therapy vectors. The studies that follow expand our knowledge about the interaction of antibodies with a newly described variant of CPV in raccoons, RPV-2 (Chapter 4) and the adenoassociated virus capsid (Chapter 5). One final aspect of parvoviral biology addressed in this work is how changes in host range, antigenicity, and receptor interactions have evolved with small numbers of capsid changes in these closely related viruses. The trafficking studies in chapters 2 and 3 were performed within this contextual framework to examine the differences in the interactions of FPV and CPV with host cells. Chapter 4 describes the phylogenetic origin, host range, and receptor binding properties of several recently characterized parvovirus strains isolated from raccoons, and places this animal as an important intermediate host in the evolution of CPV. Finally, two of the more dissimilar serotypes of AAV were examined in Chapter 5 to look at the interaction of antibodies with capsids displaying somewhat different surface features.
Virus Entry; Virus Evolution; Anti-viral Immunity
Parrish, Colin Ross
Brown, William J; Flaminio, Maria Julia Bevilaqua Felippe; Denkers, Eric Young
Ph. D., Veterinary Medicine
Doctor of Philosophy
dissertation or thesis