The work of viruses on video
A real-time color biosensor demonstrates how viruses attack healthy cells
Maria Tolmacheva, XX2 century
Viruses come in different shapes and sizes and use different attack mechanisms to enter the body. But all viruses have something in common: they can cause harm only by replicating inside the cells of another organism – their host. A team of American scientists tried to visually simulate and mathematically figure out all aspects of the virus attack strategy, including how viruses invade host cells that produce proteins. Their work can improve the understanding of all types of viral diseases and make it easier for doctors to predict and combat them.
Laboratories of Professors of the Department of Biochemistry and Molecular Biology Tim Stasevich and the Department of Chemical and Biological Engineering Brian Munsky of the University of Colorado (Colorado State University, CSU) for several years, they have been studying how viruses cause host cells to reproduce them. In the new work, the researchers demonstrated for the first time an important mechanism of virus attack on the host, at the level of a single molecule in living cells, and reproduced this behavior in computational models. Experimental results and models published in the journal Nature Structural and Molecular Biology (Koch et al. Quantifying the dynamics of IRES and cap translation with single-molecule resolution in live cells – VM), show in unprecedented detail how viruses initiate the translation of genetic material into proteins.
Capture of Ho zyain
Since viruses cannot replicate on their own, they capture the host ribosomes, which are necessary to produce proteins from the genetic material contained in RNA. Many viral genomes contain special RNA structures, ribosome internal landing sites, or IRES, that capture host ribosomes, forcing them to produce virus proteins.
CSU researchers have invented a biosensor that can detect when a cell's ribosome produces its proteins and when it produces viral ones. The sensor glows green when the cell is "healthy" and blue when it produces a virus protein. This design allows scientists to distinguish between normal host processes and viral processes in real time.
A single cell with different types of translation marked with different colors. A picture from the press release of Color-coded biosensor illuminates in real time how viruses attack hosts - VM.
The sensor combines the corresponding virus particles (but not the whole virus) that interact with the host ribosomes and "steal" them, as well as two separate protein tags that glow at the time of RNA translation. The first author of the study, PhD student Amanda Koch, has been developing the sensor for more than a year in order to study the translation of host RNA and virus RNA simultaneously.
Luis Aguilera, a graduate student in Mansky's laboratory, built a detailed computational model describing what was captured by a video microscopy taken by Koch. By analyzing Koch data through the lens of dozens of hypotheses and millions of possible combinations, Aguilera discovered complex biochemical mechanisms that biochemists could not directly see. His models showed that both healthy human RNA and viral RNA fluctuate between states when proteins are actively expressed and states when proteins are "silent".
Cellular stress
In addition to studying viral translation in normal cells, the Koch biosensor allows researchers to visualize the effects of various types of stress that cells are exposed to when attacked by a virus, as well as how, where and when viral translation increases or decreases. The integration of Koch microscopy data and Aguilera computational models showed that the relationship between normal and IRES-mediated translation is largely one–sided - normal translation dominates in healthy cells, and IRES translation dominates in cells under stress.
The Stasevich and Mansky teams suggest that the combination of their unique biochemical sensors and detailed computational analyses could become a powerful tool for understanding, predicting and controlling how future drugs might work to inhibit viral translation without affecting host translation.
Future applications to COVID-19
Researchers look to the future: they targeted COVID-19, even though SARS-CoV-2 does not contain IRES.
"Our biosensor is modular and can easily incorporate parts of SARS-CoV-2 to investigate how it uniquely captures host ribosomes during infection. Koch says. "We can take a closer look at the dynamics of how viruses penetrate into the host organisms in order to infect as many cells as possible and make us sick."
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