Scientists at The University of Texas Medical Branch at Galveston (UTMB) have employed an unlikely partner in their quest to develop treatments for COVID-19 disease: the common firefly.
Fireflies, also known as lightning bugs, are insects in the Lampyridae family who use bioluminescence to attract potential mates and prey. Their conspicuous glow at twilight comes from an enzyme called luciferase, which can be isolated in the lab. Now, UTMB virologists are using the enzyme to develop faster and more accurate diagnostic tests for COVID-19 as well as to analyze potential therapies and gain a clearer understanding of the SARS-CoV-2 virus itself.
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We are very much interested in using basic research knowledge to develop systems to support translational work, for example, diagnosing disease, vaccine development, medical countermeasures and therapeutic drugsall those things that can be applied to the public health and human well-being, said Pei-Yong Shi, Ph.D., professor of human genetics in the department of biochemistry and molecular biology at UTMB. He is leading the research by labeling viruses with glowing tags like luciferase to study them.
Prior to the SARS-CoV-2 outbreak, Shis team had been focused on flaviviruses, including West Nile virus, Zika and dengue. His lab developed the first infectious clones of the epidemic strain of both West Nile and Zika and have established new pathways for flavivirus vaccine and drug discovery.
But as the COVID-19 pandemic swept the globe, Shis lab adapted by altering research techniques to address the SARS-CoV-2 virus.
First, researchers harnessed luciferase to develop faster diagnostic testing through innovative assaysinvestigative procedures that measure the activity or amount of a substance. The lab can now visually confirm the presence of antibodies that can block a SARS-CoV-2 infection earlier than through previous methods.
The great thing about luciferase, and the one that we specifically use which is nanoluciferase, is that its really bright, said Coleman Baker, a fourth-year graduate student in the department of microbiology and immunology at UTMB who works in the Shi lab. We found that these detection assays can be read earlier than most people thought. Most people would do these 24 to 48 hours after infection and we found that you can read them as early as 4 hours post-infection.
Not only does the enhanced brightness provided by luciferase decrease turnaround time for a diagnosis, but it also helps speed up the process of vaccine development.
For vaccine studies, you need to find out how much of a response somebody has to a potential vaccine, Baker said. So, instead of the traditional waywhich could take dayswe can get results in four hours after infection.
Shi said his team has been collaborating with leading pharmaceutical companies to help them evaluate their vaccine candidates, specifically by measuring the immune response in humans in clinical trials. His labs systembased on reporter viruses in which the luciferase enzyme is inserted into the virus genome to make it easy to followmeasures the concentration of neutralizing antibodies while also allowing for a much higher throughput. According to Xuping Xie, Ph.D., assistant professor in the department of biochemistry and molecular biology at UTMB, this way of measuring the immune response is more accurate than traditional methods.
The sensitivity and the dynamics of the assay, because of the luciferase, can really allow us to discern any small changes that the conventional way would not, said Xie. Its much more sensitive, much more accurate, when you test antiviral compounds.
The compounds to which Xie is referring are potential therapies, including antiviral drugs already on the market for non-COVID-19 viral infections.
The researchers recently tested every antiviral drug approved by the FDA for human use to see if any were effective against SARS-CoV-2.
These assays allow us to very rapidly look at each in a very sensitive way very accurately, Shi said. Thats really allowed us to decide whether there is a potential so-called repurposing of these drugs for COVID-19 treatment, including remdesivir, chloroquine and others.
The virologists also have created a system for manipulating and studying SARS-CoV-2 itself, paving the way for a deeper understanding of what happens when the virus enters the human body.
Because of this system we created, we can study and understand the virus in ways that others cannot, Baker said. We have the ability to go in and make changes in the virus and see what those changes affect in the different cells that its infecting. So, not only have we developed these assays to look at drugsto look at antibody responsesbut we also are probing the virus itself and looking at how it interacts with the immune system.
Even more, the team is studying the virus genome to analyze how it has evolved and what that means for human healthincluding how it affects the body and how it transmits among different populationsusing techniques they developed for studying Zika and its connection to microcephaly, a neurological condition in which an infants head is significantly smaller than other infants of the same gender and age.
When we manipulate the viruses, it allows us to address a lot of important questions, such as how the virus is adapting and changing over time, Shi said. For example, SARS-CoV-2 now has been spreading in humans for six monthshas the virus changed? Do these changes affect viral transmission and disease severity? Scientists around the world have been chasing the virus to answer those exact questions.
Shi noted that his lab is sharing innovations with scientists worldwide to help advance public health efforts as quickly as possible.
He hopes his research will light the way.
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