Using powerful computer tools and cryo-electron microscopes, researchers at Baylor College of Medicine unmasked the secrets of a tiny virus that infects bacteria and, in doing so, opened the door to a better understanding of a variety of viruses that infect people and animals.
In a report that appears in and on the cover of the current issue of the journal Nature, Dr. Wah Chiu, professor in the BCM department of biochemistry and molecular biology and director of the National Center for Macromolecular Imaging, and his colleagues, describe how they were able to look beyond the highly symmetrical ball-like surface protein shell of the episilon15 bacteriophage that infects Salmonella bacteria and describe different molecular parts involved in binding to host cells, injecting DNA into the cell and packaging it during the virus formation.
"This methodology, in theory, can be applicable to other kinds of human viruses," said Chiu. In fact, he said, this bacteriophage appears structurally similar although smaller than the herpes simplex virus, which causes cold sores and related infections. That means it should be possible to use these tools to understand better how this and similar viruses infect nerve cells and, some day, interrupt that disease process.
The advance occurred because of innovations in computational method development in addition to the powerful cryoelectron microscopes operated at very low specimen temperature and very high energy that Chiu and others use in their work that looks at different biological nano-machineries at the nanoscale.
In fact, Dr. Wen Jiang, previously trained in the BCM Graduate School for Biomedical Sciences' Graduate Program in Structural and Computational Biology and Molecular Biophysics (SCBMB), developed a new image reconstruction algorithm. These developments enabled him and his co-authors at MIT to see through the bacteriophage at very high resolution. "It turns out that, in addition to the surface protein, there are other proteins that make this virus viable," said Chiu. In particular, proteins protruding at one of the twelve vertices of the virus shell contain structures like tails that actually anchor the bacteriophage to the surface of the bacteria itself. The shape of these "tail" structures gives clues about how the virus or phage and cell interact.
Then as Chiu and Jiang used the computer visualization tool to strip away the surface shell entirely, they saw the concentric coil of DNA underneath. They also identified a protein "hub" through which DNA enters and exits the virus.
"It's like a garden hose, in some ways," said Chiu. "You extend it. If you put it away in a heap, then you have trouble using it again. But if you coil the hose orderly, then it is easy to use again. I think the virus does the same thing. The virus genome has to enter the capsid during the birth of the virus and then inject into the cell during infection. It has to come in and get out easily. The hub anchors the tail spikes, but is also a conduit for the DNA to get in and out."
Below is the "portal" that acts as a motor using energy to coil the threads of double-stranded DNA. Using the capabilities of his program, Chiu and colleagues identified 12 protein copies that make up this viral motor.
Chiu anticipates using the same technique to study other spherical viruses as soon as he can obtain the computer power to study larger structures. Soon, he said, he hopes to be able to study the interactions of virus and cell more closely.
Others who participated in his study include Juan Chang (a current graduate student in the SCBMB Program) and Joanita Jakana of BCM, Dr. Peter Weigele and Professor Jonathan King of the Massachusetts Institute of Technology. Jiang is now a faculty with Purdue University.