Research in our lab mainly focuses on the structure, assembly and replication mechanism of RNA viruses. Usually having a relatively small genome, RNA viruses are known to infect various hosts ranging from bacteria, yeast to human. A common feature about RNA viruses is that they all encode an RNA-dependent RNA polymerase that catalyzes both replication and transcription of the viral genome. Using a combination of biochemical methods, electron microscopy, X-ray crystallography and other biophysical approaches, we aim to elucidate fundamental infection mechanisms of these viruses that will ultimately lead to better prevention and control of viral diseases.
Several RNA viruses are currently under study in our lab, including Orsay virus, influenza viruses, picobirnavirus, CcFV-1, dinornavirus, and human astrovirus. Detailed information is provided for several projects as described below.
1. Human astrovirus. Astroviruses are small, non-enveloped, icosahedral viruses with a plus-sense, single-stranded RNA genome. Astroviruses infect humans, mammals and birds, thus imposing huge impact on human health and animal wellbeing. The ~7kb genome of astrovirus encodes three viral proteins: the nonstructural protein nsp1a and nsp1ab and the viral capsid protein CP. Our laboratory recently determined the structure of the CP core and surface spike, which reveal unexpected structural homology between the CPs of astrovirus and the hepatitis E virus. Astroviruses released from infected cells require further proteolytic processing of their CP by host extracellular proteases for maturation. Ongoing research are being carried out to identify capsid structural changes and novel molecular factors that enables virus infectivity upon protease treatment.
2. Orsay virus. Orsay is the only known virus capable of naturally infecting Caenorhabditis elegans (C. elegans), a key model organism in biological research. The chronic, non-lethal nature of Orsay infection combined with the ease of
handling C. elegans provides an excellent opportunity to characterize virus infection in an intact animal. Orsay has a +ssRNA genome that encodes the putative viral RNA polymerase, the viral capsid protein (CP), and a nonstructural protein δ. The δ ORF can also be expressed as a CP-δ fusion protein through ribosomal frameshift. Work from our lab revealed that CP-δ forms a pentameric fiber that is incorporated into the infectious virion. In addition, we have established that the CP-δ head fiber mediates receptor binding and host entry, while the free δ protein is important for nonlytic viral egress. Our long-term goal is to obtain a comprehensive, molecular understanding of the Orsay life cycle using a combination of techniques including worm genetics, biochemistry, virology and structural biology.
3. Influenza viruses. Influenza viruses are a serious threat to global public health. Influenza viruses are grouped into four genera: influenza viruses A, B, C, and D (IAV, IBV, ICV, and IDV). IDV, a novel influenza virus first isolated in 2011, has been found to infect swine, cattle, and small ruminants globally, with cattle as a natural reservoir. Previous studies on IAV NS1 indicate this multifunctional protein is associated with numerous strain-specific regulatory functions affecting virus replication, pathogenesis, virulence, and host range. However, IDV NS1 lackssequence similarity to IAV NS1, raising the important question on whether IDV NS1 retains similar structure and function. Furthermore, it is predicted that IDV matrix protein M1 and the channel protein M2 are generated through a unique combination of mRNA splicing and signal peptidase cleavage, but mechanistic details and impact of these viral proteins on IDV replication are unclear. The overarching goals of this project are to elucidate the molecular mechanisms of IDV replication and pathogenesis by primarily focusing on the structure and function of NS1 and M1.