Rachel Fearns, PhD
BS, University of Leeds
PhD, University of St. Andrews
Postdoctoral Training, National Institutes of Health
Our research focuses on transcriptional and genome replication of respiratory syncytial virus (RSV). RSV is a highly prevalent virus that is the major cause of respiratory tract disease in infants and young children. Its genome structure is closely related to a number of other significant human pathogens, such as measles, mumps and parainfluenza viruses and emerging highly pathogenic viruses, such as Nipah and Ebola viruses. Understanding the molecular mechanisms underlying transcription and genome replication of RSV might help develop antiviral drugs and vaccines to treat and prevent RSV disease, and give insight into how related viruses could also be controlled.
The RSV genome consists of a single strand of negative sense RNA, which is transcribed and replicated by the virus RNA-dependent RNA polymerase in the cytoplasm of the host cell (Fig. 1).
Transcription and replication are quite different processes. Transcription yields ten subgenomic mRNAs, which are capped and polyadenylated. In contrast, replication produces antigenome and genome RNAs, which are full-length and encapsidated with virus nucleoprotein. Transcription and replication are both initiated from a single promoter region at the 3´ end of the genome and it is currently unclear how the polymerase is controlled between these two activities. In previous studies, we characterized this promoter region and identified sequences that signal polymerase recruitment and initiation, encapsidation, and mRNA initiation (Fig. 2).
Our current focus is to elucidate the molecular mechanisms by which the polymerase and its associated proteins recognize the genome and interact with these cis-acting signals to initiate either transcription or replication.
Specific questions we are tackling are:
- How does the polymerase access RNA signal sequences within the nucleoprotein-RNA structure (Fig. 3)?
- How do the cis-acting signals in the promoter region function and which proteins do they interact with?
- Is the mechanism for RNA strand initiation the same during replicative RNA and mRNA synthesis?
- What are the components of the polymerase and how is its activity impacted by the cellular environment?