research

Nearly all human genes are alternatively spliced. In the battle of pathogen and host, splicing adds a transient toggle to modify transcript levels or the surface, lifetime, or localization of a protein. Influenza virus is our model system for asking how infection reshapes splicing, and how the host pro- and antiviral factors produced are transcriptionally regulated and function.

How does the novel ISG15 splice isoform function?

Through long-read RNA-seq we identified an interferon-responsive ISG15 alternative transcript isoform producing an N-terminally truncated protein. ISG15 is widely studied in antiviral immunity, but this new variant functions independently of previously defined ISG15 roles.
Preprint → A novel ISG15 transcript restricts influenza A virus infection, bioRxiv

Can hosts hide antiviral function within essential genes?

Viruses commonly exploit essential genes for pro-viral activities. We found that the metabolic enzyme MECR contains an alternatively spliced isoform that liberates it from the mitochondria to target the flu polymerase directly. It’s a hint that hosts may safeguard antiviral proteins by embedding them within genes a virus can’t afford to disrupt.
Publication → Alternative splicing reveals a cryptic antiviral protein embedded in a metabolic enzyme, PLOS Biol.

How do ANP32 proteins contribute to viral polymerase function?

ANP32A is a critical host determinant: the avian version stimulates avian-adapted influenza polymerase, but human ANP32A does not. We found that splicing augments ANP32A stimulatory capacity, suggesting certain bird species may “pre-adapt” circulating avian influenza viruses before they ever reach a human host.
Publication → Natural ANP32A splice variants differentially stimulate the flu polymerase, Cell Rep. · ANP32B, or not to be, that is the question, eLife Insight

What differentiates promiscuity of influenza A and B viruses?

Reassortment, or swapping whole genome segments between co-infecting viruses, is a major driver of influenza virus diversity. Influenza A and B viruses both infect and cause disease in humans, but they don’t reassort with each other. There are many more influenza A virus species and rampant intratypic reassortment, perhaps contributing to the vast host range of influenza A, but not influenza B viruses.
Publication → Packaging Signals Impede Influenza A and B Virus Reassortment, J. Virol.

Building better tools to watch it all happen

Bulky reporter proteins often come with fitness costs when engineered into a virus. Our tandem split-GFP approach strings GFP11 fragments together to boost brightness while minimizing the hit to viral fitness — a tool we and others can use to watch splicing-linked host factors in action during a real infection.
Publication → Tandem split-GFP influenza viruses are fit & bright, Microbiol Spectr.

For a full list of publications, see Google Scholar or NCBI Bibliography.