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HOST SPECIES-SPECIFIC INHIBITION OF THE ANTIVIRAL PROTEIN KINASE R BY POXVIRAL PSEUDOSUBSTRATE INHIBITORS
- Park, Chorong
- Advisor(s): Rothenburg, Stefan SR
Abstract
Viral host range is highly divergent, and we are just beginning to grasp how the intricate network of virus-host interactions determines host range. To be called a host range, viral life cycle from entry to exit and transmission between organism-to-organism should be fulfilled. A variety of factors contribute to cross-species transmission. Complex external factors (seasons, social behaviors, geographic traits and more) provide a stage where hosts and viruses encounter and create genetic variations through constant interactions between two entities. Genetic variations can increase viral fitness in one organism and sometimes allow transmission across host species. With the advance in genomic analysis combined with biological experiments, our understanding of how host-virus interactions occurs through antagonistic interactions has also improved. Poxviruses are dsDNA viruses infecting a wide range of vertebrate and invertebrate host species which makes poxviruses an ideal model to study host-virus interactions and co-evolution. Host genes, often related to host immune responses, activated by and interacting with viral gene products, have been especially useful to study co-evolution. Amongst poxviridae, my thesis work focused on two genera: orthopoxviruses capable of productively infecting diverse host species and capripoxviruses that infect mainly ungulates. Protein kinase R (PKR), a host innate immunity gene, is well known to be one of the critical antiviral factors limiting poxvirus infections by shutting down the host translation system. Accordingly, many poxviruses encode PKR inhibitors, E3L and K3L, also known as host range genes. In addition, K3L is not required for viral replication in human cells but indispensable in Syrian hamster cells; this finding demonstrates differential requirement of specific PKR inhibitors depending on the host species. This research investigated the role of K3L from two poxviral genera, orthopoxviruses and capripoxviruses, in PKR species-specificity and its relationship to host range. Furthermore, we extended the analysis of the molecular mechanism for PKR and K3L interaction using selected viral and host species. Collectively, this work provided experimental evidence of poxviral K3L function in host range and the implications of this function in host-virus co-evolution.
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