Price’s research focus is on how DNA viruses co-opt and manipulate cellular RNA processing pathways.
Growing up on the west coast, Price obtained his Bachelor’s of Science degree in Genetics and Cell Biology at Washington State University. Moving to the east coast, he obtained a Ph.D. in Molecular Genetics and Microbiology from Duke University in 2016. To pursue postdoctoral research, Price moved to Philadelphia, where he was associated with the University of Pennsylvania and the Children’s Hospital of Philadelphia. In 2023 he joined the Wistar Institute as an Assistant Professor in the Gene Expression and Regulation Program.
The Price Laboratory
Research
QUESTION 1: HOW IS NUCLEAR DSRNA SENSED AND RESPONDED TO DURING VIRAL INFECTION?
Viruses with limited genome size maximize coding capacity via regulated expression of genes on both DNA strands. It is thought that convergent transcription of DNA virus genomes leads to the production of dsRNA, and this postulate is supported by the fact that these viruses encode inhibitors of dsRNA sensing pathways. However, there is little primary evidence of dsRNA accumulating during DNA virus infection. In my prior work I utilized monoclonal antibodies directed against dsRNA to examine cells infected by adenovirus, yet I was unable to detect dsRNA. However, infection with adenovirus mutant viruses that exhibit inefficient splicing of viral transcripts leads to robust dsRNA production in the nucleus. The presence of nuclear dsRNA during mutant adenovirus infection is accompanied by activation of cytoplasmic sensors PKR and RNase L, yet there is no known nuclear sensor of dsRNA. Assessing the role of nuclear dsRNA sensing is becoming increasingly important as it is more appreciated that hyperactivity of cellular antiviral sensors can lead to autoimmune disease. Specific questions include:
- How Is nuclear dsRNA sensed by the innate immune system?
- How does nuclear recognition of dsRNA communicate with existing components of the immune system?
- How do nuclear dsRNA-binding proteins interact with viral dsRNA?
QUESTION 2: HOW DO DNA VIRUSES SPATIALLY REGULATE RNA TRANSCRIPTION AND PROCESSING?
Unprocessed adenoviral RNAs are likely to form dsRNA if they are synthesized in close proximity to antisense transcripts. Viruses that can regulate sense and antisense transcription in spatially distinct nuclear compartments would allow for localized processing that would preclude dsRNA formation. It was previously shown that viral DNA replication takes place inside biophysical viral replication centers, and that RNA synthesis occurs in a shell surrounding these regions. However, how this spatial segregation occurs is unknown. Specific questions include:
- How are viral genomes spatially organized?
- How do DNA viruses spatially regulate RNA transcription?
- Does transcription of viral genomes lead to viral mutation or genome instability?
QUESTION 3: HOW DO HERPESVIRUSES EXPLOIT RNA PROCESSING?
Herpesvirus lytic transcripts are often intron-less and bypass many canonical processing steps on the path to expression. Viral RNA-binding proteins, whose functions are only recently being fully understood, often mediate these processes. In contrast, latent phase infection encodes complex transcripts with extensive alternative splicing reliant on cellular factors for expression. Furthermore, herpesvirus latency transcripts are prime targets for uncovering novel roles for non-coding RNAs, as they are often expressed in the absence of viral proteins. Projects will be available in the lab to study both the RNA-protein and RNA-RNA interactions of these transcripts using advanced proteomic and sequencing technologies.
