We study the untapped repertoire of alternatively spliced antiviral genes.
As viruses spill over into humans, differences in host factors force them to adapt to this unfamiliar territory. Nearly all human genes are alternatively spliced. A major driver to host-specific protein differences can be attributed to alternative splicing. Our research uses influenza virus as a model to explore how virus infection triggers changes in alternative splicing, and how virus pro- or anti-viral factors are posttranscriptionally regulated.
Below are a few publications from Steve’s postdoc with Andy Mehle in Madison, WI and graduate studies with Luis Martínez-Sobrido in Rochester, NY that represent where the lab is looking to continue.
Cryptic isoform of MECR antagonizes influenza virus.
Viruses commonly exploit essential genes for proviral activities. The metabolic enzyme MECR contains an alternatively spliced isoform that liberates it from the mitochondria to target flu polymerase. This observation may hint at hosts safeguarding antiviral proteins by embedding them within essential genes.
ANP32B, or not to be, that is the question.
We put in context several observations made regarding the host proviral ANP32 family member genes. Focusing on the publication from Long et al., we show important amino acid differences that help support influenza virus polymerase activity from these whip-like proteins.
Natural ANP32A splice variants differentially stimulate the flu polymerase.
The critical host determinant ANP32A from birds stimulates avian-derived influenza polymerase, but human ANP32A does not. We explore how ANP32A functions (it stimulates intrinsic polymerase activity) and whether certain birds may “pre-adapt” circulating avian influenza viruses to jump to humans.
Why don’t FLUAV and FLUBV reassort?
Reassortment is a major driver of influenza virus diversification where whole genome segments of similar viruses are swapped during coinfection. Though influenza A and B viruses (FLUAV and FLUBV for short) both infect and cause disease in humans, they don’t reassort. We found that viral packaging signal incompatibility cements virus speciation.