Chung, associate professor in the UofL Department of Microbiology and Immunology and the , and colleagues at the University of Wisconsin–Madison’s School of Pharmacy and the University of Tennessee Health Sciences Center (UTHSC) described their work with BDGR-49 in a in Science Translational Medicine.

Chung led chemical virology studies, Jennifer E. Golden, associate professor in the UW–Madison School of Pharmacy and synthetic medicinal chemist, led the discovery and optimization effort and Colleen Jonsson, a professor at UTHSC, performed animal efficacy studies.

The team found that BDGR-49 potently inhibited EEEV and VEEV and was well tolerated. The compound provided significant protection to EEEV-infected animals. Meanwhile, it not only fully protected VEEV-infected animals, but could also be used as a therapeutic treatment days after infection.

An important feature of this antiviral compound is its ability to access the brain where these viruses cause damage, while other critical attributes include its improved stability, potency and efficacy compared to earlier prototypes. Based on resistance studies, BDGR-49 efficiently prevents these viruses from copying themselves, meaning it operates by disrupting the viral machinery needed for replication. 

Classified as New World alphaviruses, equine encephalitis viruses are transmitted by the bite of a mosquito and can infect the brain, causing neurological effects, serious illness and death in humans as well as horses. There currently are no FDA-approved vaccines or treatments available specifically for preventing or treating alphavirus infection in humans.

Symptoms of EEEV infection include fever, headache, chills and vomiting. Severe infection can result in seizure, coma and death. About one-third of individuals who develop encephalitis (brain inflammation) from EEEV infection die, and many of those who do recover suffer permanent neurological effects.

Although outbreaks of eastern equine encephalitis (EEE) are rare, with an average of 11 cases per year in the United States, a 2019 outbreak of EEE across nine states resulted in 38 confirmed cases, 19 deaths and neurological effects in survivors.

VEE has a much lower mortality rate of 1%, but outbreaks can affect thousands of people, most often occurring in Central and South America. While insect bites are the typical cause of these infections, there is also concern the viruses could be leveraged as bioweapons.

“What we are trying to do is to develop a drug that can be used to treat infected people or as a prophylactic in case of bioterrorism,” Chung said. “Now we are seeing that it protects from lethal infection. This is a big milestone in terms of the therapeutic development.”

Chung, Golden and Jonsson have been developing chemical structures against VEEV and EEEV for more than a decade. They are co-investigators in the Center of Excellence for Encephalitic Alphavirus Therapeutics, based at UTHSC. The center was created to refine the properties and activity of early-stage small molecule compounds discovered in the Golden lab and to develop them into clinical candidates for VEEV and EEEV that could be studied in humans. This work received a five-year, $21-million grant from the National Institutes of Health in 2019.

The team now is evaluating BDGR-49 in advanced preclinical studies and expanding the understanding of its antiviral properties. As RNA viruses such as EEEV and VEEV are prone to develop mutations, they can potentially evolve into more lethal or transmissible versions without warning, resulting in widespread infections.

“It is essential that we develop these countermeasures for viruses of pandemic potential so we don’t find ourselves unprepared to respond to an outbreak,” Golden says. “We can do better, and we intend to leverage this discovery as broadly as possible with respect to VEEV, EEEV and other viruses of concern.”

This research was supported by the National Institute of Allergy and Infectious Diseases (U19AI142762 and R01AI118814) and by a grant (S10OD016226) from the Office of the Director of the NIH.

In an article published last week in , Yousef Abu Kwaik, PhD, professor, and Chris Price, PhD, senior research scientist, both of the Department of Microbiology and Immunology, and other researchers at UofL explain that L. pneumophila uses the same mechanism or virulence determinant in both amoeba and the accidental human host, but with different results. A virulence determinant is a gene or protein that plays a key role in disease development.

Legionnaire’s disease is a type of pneumonia caused by the bacterium L. pneumonphila. Legionnaire’s disease, named for one of the first documented outbreaks of the infection at an American Legion convention in Philadelphia in 1976, accounts for approximately 15 percent of pneumonia cases worldwide and has a mortality rate of 20 to 50 percent. L. pneumophila evolved as an environmental bacteria that lives in water, surviving and proliferating in several species of amoeba as its natural hosts. It is the only bacterial pathogen for which amoeba are the natural hosts and humans are accidental hosts.

The bacteria are transmitted to humans who accidentally inhale them in water particles that have been aerosolized by man-made devices such as cooling towers, whirlpools, fountains or misters such as those used in grocery stores or in water parks. These devices distribute the water particles into the air along with bacteria that may be present in the water.

The bacteria are transmitted to humans who accidentally inhale them in water particles that have been aerosolized by man-made devices such as cooling towers, whirlpools, fountains or misters such as those used in grocery stores or in water parks.

When L. pneumophila enters its natural amoeba host, it injects a protein into the single-celled organism that prevents the amoeba from destroying the bacteria and provides a safe home in which the bacteria may grow and spread. When L. pneumophila enters human lungs, it injects the same protein into alveolar macrophages. Contrary to the outcomes in the amoeba, the bacterial protein stimulates an inflammatory response in human macrophages that contributes to pneumonia. This effect is counterproductive to the bacteria as it stimulates the human host to restrict the invading bacteria. The effect of the injected protein in human cells also contradicts evolutionary co-existence of the pathogen with the human host, which is considered an accidental host. The injected bacterial protein has evolved in Legionella to interfere with a specific process in the amoeba host that does not exist in the more evolved human cells, where a paradoxical effect is mounted in response. 

“Our findings show for the first time that a bacterial ‘tool’ has evolved exclusively to manipulate an amoeba host-specific process, but it has a paradoxical effect on the human host,” Abu Kwaik said.

This knowledge may lead to methods that help reduce the bacteria’s ability to survive in amoeba in water sources, limiting the transmission of Legionnaire’s disease.

“Since the bacteria are not transmitted from one person to another, we have the opportunity to prevent transmission by targeting the bacterial protein with small molecule inhibitors,” Abu Kwaik said. “That would enable the amoeba to restrict and degrade the bacteria, blocking their amplification in the water system and, in turn, abolishing accidental droplet transmission to humans.”

“Fermentation science goes beyond the microbiological aspects related to yeast, lactic bacteria used in the sour mash process and the control of microbial contaminants. Other biological processes we must wrangle are grains, grain quality and the enzyme systems in malted barley, which are critical to breaking starches in grain down to metabolizable sugars,” said Smith, a Louisville native who earned a master’s degree in environmental microbiology from UofL. 

Smith will explain how modern yeast handling practices and industrial equipment for distillery sanitation allow for improved consistency, quality and sensory character of new whiskey. He also will describe how individual yeast strains affect a whiskey’s flavor.

The event begins at 8 p.m. on Wednesday, April 5, at Against the Grain Brewery, 401 E. Main St. in Louisville. A 30-minute presentation will be followed by an informal Q&A session.

Admission is free. Purchase of beer, other beverages or menu items is not required but is encouraged.

For more information and to suggest future Beer with a Scientist topics, follow Upcoming dates: 

• May 17 – Gerard Williger of UofL – The coming solar eclipse and mapping asteroids
• June 14 – Jacquelyn Graven, Graven and Assoc. – How to work less and play more
• July 12 – Lee Dugatkin of UofL – How to tame a fox and make a dog