Early stage viral infection

Unexpected disease outbreaks caused by rare infectious agents from different continents have been a real threat in our lives. Furthermore, to fight against diseases, specially engineered viruses are used as the vaccine. It is therefore vital to understand how a virus infects a cell and how it initiates the immune response. We use advanced optical microscope techniques to study virus-membrane interaction at ultrahigh spatiotemporal resolution.
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Viral infection is a highly complicated process. Virus particle has to attach to the cell surface, penetrates the cell plasma membrane, delivers the viral genome into cell cytosol for replication, and eventually releases the many copies of virus particles from the infected cell. By molecular biology approaches, many proteins and enzymes required for successful viral infection have been identified. Through fluorescence microscope techniques, viral infection can now be monitored in real time. Although a lot have been learned about viral infection, some of the most fundamental questions of virus-cell interaction remain elusive. For example, how does a virus find a receptor in the plasma membrane? How does a virus activate a membrane receptor? To unveil the virus-cell interaction with molecular clarity, ultrahigh sensitivity and spatiotemporal resolution are needed simultaneously.
 

Combining molecular biology approaches and advanced optical microscopy, we (our lab and Dr. Wen Chang's lab at the Institute of Molecular Biology, Academia Sinica) have been investigating virus-receptor interaction in the early-stage viral infection. Recently, using the ultrahigh-speed optical technique developed in our lab, we successfully captured the dynamic process of single vaccinia virus particles attaching to the cell plasma membrane at ultrahigh spatial precision and temporal resolution. From such measurements, we are able to study the virus-membrane interaction at the molecular length scale and microsecond timescale for the very first time. We observed that the vaccinia virus particle is confined within a zone of hundreds of nanometers in diameter within a second after attachment. Interestingly, under our ultrahigh-speed observation (100,000 frames per second), we found that within the confined zone, the virus laterally explored the plasma membrane at very high diffusion coefficient and meanwhile got transiently trapped at numerous nanoscopic sites. These transient (sub-millisecond) nano-confinements might be the results of virus-receptor interaction.

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