By Pat Bailey
Hannah Laurence, a third-year student in the UC Davis School of Veterinary Medicine and a Howard Hughes Medical Institute fellow, had the privilege of doing biomedical research during the past year in the laboratory of Professor Jeff Kieft at the University of Colorado School of Medicine.
Recently, the Kieft lab announced in the journal Science discovery of the molecular process used by the Zika virus to “hijack” the cells that it infects and potentially how the virus makes molecules that are directly linked to disease.
The discovery shows that a part of the Zika virus’s RNA genome folds up into a complex structure and that this structure leads to the production of smaller RNAs, which in related viruses are directly associated with disease.
“Stepping out of the veterinary curriculum for a year was challenging but ultimately an extraordinary experience, Laurence said. “Over the course of the year, not only did I have the opportunity to be a part of an incredible research team, but also together we were able to address fundamental questions about the structure and function of Zika virus. We hope that our findings will set the groundwork for future studies on therapeutics for Zika and related Flaviviruses.”
Laurence, who completed her undergraduate studies at Colorado State University before coming to UC Davis, was one of 68 top medical and veterinary students chosen last year from 37 different schools in the nation to conduct full-time biomedical research in the HHMI’s Medical Research Fellows Program.
Discovering how Zika virus works
Because viruses cannot reproduce on their own, they must infect cells and take over the cell’s biological machinery to make more copies of themselves. To do this, viruses use many molecular strategies.
Zika is an example of a virus that does not store its genome in DNA, rather it uses a related molecule called the viral genomic RNA. Viruses related to Zika, such as West Nile and Dengue, are known to produce a set of smaller RNAs that are directly linked to disease, as well as long genomic RNA. Before this study, this process had not been explored with the Zika virus.
In the new study from the University of Colorado School of Medicine, the researchers showed that Zika infection leads to production of these smaller RNAs in several types of cells. In addition to demonstrating how the Zika genomic RNA “folds up” and blocks a powerful cellular enzyme that normally destroys RNA, the research team used an advanced technique called x-ray crystallography to solve the structure of this folded-up RNA segment.
By altering the Zika virus genomic RNA, the team was able to disrupt this structure and eliminate the production of the potentially disease-causing small RNAS.
“The first step in stopping any process that causes disease is to understand that process in detail, preferably at the molecular level,” said Professor Kieft, corresponding author on the study and a member of the University of Colorado RNA BioScience Initiative. “Based on what we knew about related viruses, there was reason to suspect that Zika virus infection would result in potentially disease-causing RNAs, but we couldn’t be sure. Now, having observed them and the molecular structures involved, we can ask new questions about the fundamental molecular processes Zika uses to take over a cell and cause disease.”
Lead author on the study was Benjamin Akiyama from the Kieft lab.
Kieft noted that the study findings also could inform ongoing efforts to develop a vaccine or other anti-Zika therapeutics. The discoveries also may be broadly applicable to understanding and preventing other related viruses such as Dengue, West Nile, Japanese encephalitis and yellow fever.
Pat Bailey writes about agricultural and veterinary sciences for UC Davis Strategic Communications. Follow her on Twitter @UCDavis_Bailey.