Bacteria and viruses have ways to avoid these defenses, however. Yersinia pestis, the bacteria that causes bubonic and pneumonic plague, for example, can hide from the immune system, allowing it to replicate in the body unhindered until it can overwhelm the host. This ability allowed Y. pestis to spread bubonic plague across Europe in the 14^th Century, killing a third of the European population.

While plague may not be a serious threat to human health in modern times, researchers at the University of Louisville are studying Y. pestis to better understand its ability to evade the immune system and apply that understanding to control other pathogens.

“If you look at human plague, people don’t show symptoms right away even though they have an active infection because the bacteria is hiding from the immune system. Then all of a sudden there is a lot of bacteria, the immune system is overwhelmed and in the case of pneumonic plague, the individual dies from pneumonia,” said , professor in the UofL Department of Microbiology and Immunology.

Neutrophils are the immune system’s first responders, sending out protein molecules to summon other neutrophils to attack and destroy the invader. Among the first molecules sent out by neutrophils to signal an infection are Leukotriene B4 (LTB4) lipid molecules. Y. pestis interferes with the immune response by suppressing the LTB4 signals. Lawrenz has received a new $2.9 million, four-year grant from the National Institutes of Health to investigate how Y. pestis blocks LTB4. Ultimately, he expects this understanding will lead to ways to prevent Y. pestis from blocking the signals and hopefully, apply that understanding to other types of infections.

“This historic pathogen is really good at manipulating the immune system, so we use it as a tool to better understand how white blood cells like neutrophils and macrophages respond to bacterial infection,” Lawrenz said. “In this project, we are using Yersinia to better understand why LTB4 is so important to controlling plague. This understanding would apply to almost any infection of the lungs or other areas, and it probably could apply to viruses also.”

A member of the��, Lawrenz has been studying plague bacteria for nearly two decades. His previous work includes discoveries of how Y. pestis acquires iron and zinc to overcome a host’s defense mechanism known as nutritional immunity and has increased understanding of how Y. pestis to hide from the immune system.

Katelyn Sheneman, a doctoral student in Lawrenz’s lab, also has received a prestigious $100,000 research award for trainees from the NIH. This grant will fund her research to understand how Y. pestis changes the contents of extracellular vesicles, cellular containers produced by immune cells that contain proteins, lipids such as LTB4 and other components. These vesicles are released into the bloodstream to communicate to other cells what is happening in their part of the body, such as an infection.

“My project is looking at how Y. pestis alters the number of vesicles being produced, what is being packaged in them and how other cells are responding to them,” Sheneman said. “We have some good evidence that pestis is able to manipulate the production of these vesicles, so we are going to look at the role the vesicles play in pulmonary infection and how that influence contributes to overall systemic infection.”

Since there is no effective vaccine against infection by Y. pestis and it has the potential to be used as a bioweapon, Lawrenz and Sheneman study Y. pestis in UofL’s Biosafety Level 3 facilities at the Regional Biocontainment Laboratory, part of a network of 12 regional and 2 national biocontainment laboratories for studying infectious agents. Biosafety Level 3 facilities are built to exacting federal safety and security standards in order to protect researchers and the public from exposure to the pathogens being investigated.��

The study, published Jan. 20 in , found CBD showed a significant negative association with SARS-CoV-2 positive tests in a national sample of medical records of patients taking the FDA-approved drug for treating epilepsy. The researchers now say that clinical trials should be done to determine whether CBD could eventually be used as a preventative or early treatment for COVID-19.

They caution, however, that the COVID-blocking effects of CBD come only from a high purity, specially formulated dose taken in specific situations. The study’s findings do not suggest that consuming commercially available products with CBD additives that vary in potency and quality can prevent COVID-19.

Scientists have been looking for new therapies for people infected by the coronavirus and emerging variants, especially those who lack access to vaccines, as the pandemic continues across the country and world and as breakthrough infections become more common.

“The Commonwealth of Kentucky has a robust hemp agriculture, so we were pleased to find that pharmaceutical grade CBD is worth testing in future human clinical studies,” said Kenneth Palmer, study coauthor who headed the UofL research team. “In response to the COVID-19 pandemic, our team developed expertise in SARS-CoV-2 infection models and we welcomed the opportunity to collaborate with the University of Chicago team to confirm the efficacy of CBD treatment against SARS-CoV-2.”

Palmer is director of the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases and the Leona M. and Harry B. Helmsley Charitable Trust Endowed Chair in Plant-based Pharmaceutical Research at UofL. The center houses the Regional Biocontainment Laboratory, one of only 12 regional and two national biocontainment labs in the United States and the only one in Kentucky. Established with support from the NIH to conduct research with infectious agents, the lab includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards.

Researchers from the University of Louisville co-authoring the study with Palmer are Divayasha Saxena, Jon D. Gabbard, Jennifer K. Demarco, William E. Severson and Charles D. Anderson. The research was directed by the University of Chicago and other scientists involved are from the National Argonne Laboratory, the University of Illinois at Chicago and the National COVID Cohort Collaborative Consortium.

For more detail on how medical-grade CBD shows promise as a treatment for COVID-19, check out the full story here.��

Microbiologists at the University of Louisville study Yersinia pestis, the bacteria that causes bubonic plague, however, because it has the potential to be used as a bioweapon and it provides knowledge that may help defeat other bacteria. Through this work, they have made an important discovery about a molecule secreted by Y. pestis and other bacteria that helps defeat the host’s immune defenses, allowing the bacteria to infect its hosts.

Sarah Price, a doctoral student researcher, and her mentor, Matthew Lawrenz, associate professor of microbiology and immunology, have found that yersiniabactin, a small molecule secreted by Y. pestis, gathers zinc, a necessary element for bacterial replication. This discovery may have implications in other infections as well since bacteria causing pneumonia, sepsis and other illnesses also are known to release yersiniabactin.

“While yersiniabactin’s role in iron acquisition has been well known for over 30 years, we were surprised to see its significant impact on zinc acquisition during Y. pestis infection,” Price said��“This is very exciting because it helps us understand how Y. pestis and other bacteria acquire nutrients that allow them to cause disease.”

Invading bacteria as well as the hosts they infect all require iron, zinc and other metals in order to grow. The host’s immune system employs a strategy called nutritional immunity to protect against these bacterial infections, sealing the metals away from the bacteria.

It has been known for many years that yersiniabactin defeats this defense by stealing away iron and delivering it into the bacterial cells. Price and Lawrenz have discovered that the molecule also is involved in securing zinc and perhaps even other metals to assist Y. pestis infection.

Yersiniabactin also is used by Escherichia coli, which causes a multitude of infections such as intestinal illness and kidney infections, and Klebsiella pneumoniae, which causes pneumonia and sepsis. These more common diseases can be life-threatening and multidrug-resistant infections. The new understanding may lead to additional strategies for controlling infection by all of these bacteria.

An article describing the research published Oct. 29 in ��provides details about how the researchers determined that yersiniabactin was responsible for the collection of not only iron, but zinc. Price is first author on the publication, “.” Lawrenz is senior author and researchers from the University of Kentucky, Washington State University and the University of Illinois also contributed to these studies.

“With this understanding of the broader role of yersiniabactin in plague infection, we can explore further to understand its role in enabling other bacteria to infect a human or other host,” Lawrenz said. “If this mechanism holds true across these bacteria, it may be possible to develop a drug or vaccine that could inhibit yersiniabactin’s effectiveness, thus preventing all of these infections.”

Bubonic plague most often is transmitted to humans through the bite of an infected flea, usually carried by a rodent. By not handling animal carcasses, preventing flea bites and avoiding contact with bodily fluids of those infected, the spread of bubonic plague is largely controlled. However, since human-to-human transmission is possible, mortality from an infection ranges from 30-to-90% and no vaccine is available to prevent the infection, it remains an important pathogen for research. In addition, Y. pestis, has the potential for weaponization and is considered a bioterrorism threat.

Lawrenz, Price and their colleagues conduct research within the , which focuses on the development of prevention and treatment strategies for infectious diseases and other harmful pathogens. Its researchers utilize the Regional Biocontainment Laboratory, a member of the National Institute of Allergy and Infectious Diseases network of 12 regional and 2 national biocontainment laboratories for studying infectious agents. The lab includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards to protect researchers and the public from exposure to the pathogens being investigated.��

The center’s researchers were called upon in early 2020 to develop tests and prevention and treatment strategies against SARS-CoV-2, the virus that causes COVID-19. This work continues.

Between Aug. 25 and Sept. 1, investigators from the tested nearly 3,000 Jefferson County residents for the to detect the presence of the virus in participants’ nasal swabs by the polymerase chain reaction (PCR) method and for the presence of antibodies against the virus in their blood.

The results showed that approximately 1.1% of all the participants tested positive for active coronavirus infections. Among vaccinated participants only 0.7% had an active infection, while nearly 5% of unvaccinated participants were actively infected. This number would roughly correspond to 7,260 active infections in the county, a nearly tenfold increase in infection rates over the rates measured in April, despite a sharp increase in vaccinated residents, as shown in Figure 1.

As in previous testing rounds, the team also tested for antibodies in participants. They found that independent of their vaccination status, in both the sampled and volunteer groups, nearly 16% of the participants had natural infection antibodies against the virus suggesting that they must have been infected by the virus in the recent past. These data indicate that in the last few months, at least 100,000 adults in Jefferson County have had COVID-19.

“These results highlight the steep rise in coronavirus infections in our community and provide a startling snapshot of the current state of the pandemic,” said Aruni Bhatnagar, director of the Envirome Institute. “Our estimates suggest that the number of infected individuals may be twice as high as that indicated in public records.

“Our work shows the vaccine is working as intended. Our population was almost 90% vaccinated, much higher than the 64% of fully vaccinated county residents. In the entire cohort, vaccinated people were over 12 times less likely to be infected compared with unvaccinated people. Though in our volunteer group, 65% of the active infections were in fully vaccinated individuals who had received the vaccine earlier this year. Most reported no or mild allergy-like symptoms and did not recognize that it may be a COVID infection thus did not think they needed to get tested.”

The study also provided estimates of where in Jefferson County the infections are most prevalent. To identify infection rates in different areas, the researchers classified the participants into neighborhood zones, as shown in Figure 2.

The highest rate of active infection was found in Zone 3A, or far southwestern Jefferson County. The highest rate of those recently having had an infection was found in Zone 3B, central southern Jefferson County, as shown in Figure 3.

Participants from Zone 3B also reported lower rates of vaccination, although vaccination rates were lowest in Zone 1B in western Jefferson County, as shown in Figure 4.

“Even though nearly 90% of the participants in the entire study population were vaccinated, we had areas that reported as low as 60% vaccination, and the persistence of infection in some geographical areas seems to be related to lower rates of reported vaccination,” said Rachel Keith, associate professor of environmental medicine at UofL who conducted the study. “Our results show that much work remains to be done and that knowing that rates of infection are high in their community may be an added incentive for some individuals to get vaccinated.

“Additionally, knowing that fully vaccinated individuals may still get an active infection allows those individuals to take additional precautions such as masking or testing which helps keep the community safe, including any young or immunocompromised friends and families who may need extra protection.”

“The vaccine is very effective. Nearly 96% of vaccinated individuals had detectable levels of antibodies against the virus in their blood. However, in a small number of people (less than 0.6%) the levels of antibodies were undetectable in our assay, even though these individuals were fully vaccinated,” Keith said. “The lack of a measurable response in some individuals even after vaccination may be due to their health and immune status. We are analyzing our results to find out more about why some rare individuals do not develop high antibody levels in response to vaccination.”

Using the data from more than 7,000 individuals tested over the past year, the team is trying to identify personal and environmental characteristics that increase the risk for coronavirus infection and how vaccination reduces this risk.

For this round of testing, the team collected samples at 13 locations across Jefferson County. Active coronavirus infections were analyzed by Bluewater Labs and antibodies against the virus were assayed at at the .

To randomly sample people from all parts of the city and to include proportional number of individuals of different age and race/ethnicity, researchers at UofL partnered with Westat to mail approximately 30,000 letters asking people to participate in the study. Nearly 1,000 people who responded to this invitation were tested and an additional 1,886 booked their own appointments after hearing about the study in the news or on social media.

This study was supported in part by a contract with the Centers for Disease Control and Prevention.

Throughout May, Phase I of the tested 1,372 health care workers at hospitals in the system. Samples were collected by UofL’s and tested at ��at the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases.

The study found just two participants had an active infection of SARS-CoV-2, the virus that causes COVID-19. An additional 14 workers tested positive for antibodies, suggesting that they have been exposed to the virus. Unfortunately, due to low amounts of blood in some samples, antibody levels could not be tested in 128 workers.

The Co-Immunity Project, launched in April with an announcement by Kentucky Gov. Andy Beshear, is a collaboration between the and the Brown Envirome Institute. The purpose of Phase I of the project was to test health care workers at the , and UofL Health systems to identify those who have been exposed to COVID-19 and to determine how their body produced a response, or antibodies, to such infection. This information will help identify potential donors of high-quality plasma for treatment of patients with severe COVID-19 symptoms.

Interested health care workers collected their own blood and plasma samples and delivered them to researchers with the Brown Envirome Institute. The samples were then tested at the RBL, one of only 12 such NIH-funded laboratories in the nation and the only one in Kentucky. Results from Baptist Health and Norton Healthcare will be provided at a later date, but researchers say the results from workers at UofL Health facilities provide data that can be used to provide information about the pandemic and its effects.

UofL Health consists of five hospitals, four medical centers, nearly 250 physician practice locations, the UofL Health – Frazier Rehab Center and the UofL Health – James Graham Brown Cancer Center.

“The rates of infection and exposure among our health care workers is surprisingly low,” said CPM/RBL Director Kenneth Palmer, a co-investigator of the project. “Even though the number of individuals who tested positive for the antibody is more than those who had the active virus, this is still a low number, especially for those who are working in high-risk environments such as hospitals.”

“This is good news,” said UofL Assistant Professor of Medicine Rachel Keith, who conducted the study, “It shows that the precautionary measures adopted by our hospitals are working, and that patients seeking care in our hospitals are at a low risk of being infected by their health care providers.��

“These results show the need for appropriate precautions, indicating that with proper PPE and social distancing, we can minimize the threat posed by the virus to our health care community.”

Researchers advised, however, that because so little is known about the novel coronavirus SARS-CoV-2 and the disease it causes, COVID-19, much more research is necessary.

“The rates of infection among health care workers nationwide remains unknown. A recent study of health care workers in Germany who had direct contact with COVID-19 patients did find that only 1.6% tested positive for SARS-CoV-2 antibodies. This is within range of the 1% of antibody-positive health care workers our study found in Louisville,” said Brown Envirome Institute Director Aruni Bhatnagar, a co-investigator with the project.

“However, fewer individuals with antibodies against the virus also could mean that few individuals have acquired immunity, and therefore many of our health care workers may be vulnerable to the virus still lingering in our community. They may remain susceptible should infections increase again, either in the fall or some other time.”

Individuals who have recovered from COVID-19 and have antibodies against the virus are being asked by Norton Healthcare to donate plasma to help treat high-risk patients. More information is available on the .

opened earlier this month to the community to sample 2,400 participants who reside in different parts of Jefferson County to determine the existing prevalence of COVID-19 infection and immunity in the general population.

The project also will re-test health care workers across UofL Health in July to see whether the rates of infection and immunity have changed since May. The results from this second survey will be critical in monitoring how an increase in non-critical care activities in UofL hospitals has affected SARS-CoV-2 infections and see what changes occur to the levels of antibodies in those who showed a positive antibody response in Phase I testing.

The California biomedical company Qualigen Therapeutics Inc. has signed a license agreement for the technology, and plans to fund continued development with UofL to ready it for market.

The technology, first announced in April, is based on a piece of synthetic DNA — an “aptamer” — known as AS1411, which targets and binds with a human protein called nucleolin. Early tests show AS1411 may stop viruses, including coronavirus, from “hijacking” nucleolin to replicate inside the body.

UofL researchers Paula Bates and Kenneth Palmer partnered to apply the AS1411 technology to coronavirus. Bates co-discovered the base aptamer technology with researchers John Trent and Don Miller and has applied it a variety of ways, including to .��The cancer application of the technology also is in development with Qualigen.

“This new use of the AS1411 technology, to fight coronavirus, is another example of the relationship we’ve developed with UofL and how we can work together at a high level,” Qualigen CEO Michael Poirier said. “Because of our outstanding partnership in the cancer area, we believe that our combined effort will be up to the enormous challenge with COVID-19. This is a critically important effort that could provide much needed help to COVID-19 patients worldwide. It is imperative that we do everything we can to succeed.”

Palmer, who is director of UofL’s Center for Predictive Medicine and Regional Biocontainment Laboratory, conducted proof-of-concept experiments showing the aptamer was effective against the virus at doses shown to be safe in humans by previous research.

The lab is one of only 12 regional and two national biocontainment labs in the United States and the only one in Kentucky. Established with support from the NIH to conduct research with infectious agents, the lab includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards. The stringently secure facilities protect researchers and the public from exposure to the pathogens being investigated.

“This has been a true collaborative effort — everyone at UofL has rallied together to take on this big global challenge,” Bates said. “I am fortunate to be at UofL, which is one of the few places in the country where we have the facilities to do this important work.”

Both AS1411 applications — to fight cancer and coronavirus — are licensed to Qualigen through the , which works with startups and industry to commercialize university-born technologies.

The work so far on the technology’s COVID-19 application has been partially supported by a gift from shipping giant UPS, which in early May to fund trials and test materials.

The technology is based on a piece of synthetic DNA – an “aptamer” – ��which targets and binds with a human protein called nucleolin. Early tests show that this aptamer may stop viruses, including novel coronavirus, from “hijacking” nucleolin to replicate inside the body.����

UofL is seeking to fast-track development, including application to the Food and Drug Administration for approval to start treating patients seriously affected with COVID-19.����

The aptamer was discovered by UofL’s Paula Bates, John Trent and Don Miller, who have applied it in a variety of ways, most notably as a potential therapeutic drug against multiple types of cancer.��With the current global pandemic of coronavirus and the COVID-19 disease it causes, Bates partnered with fellow researcher Kenneth Palmer to apply the technology once again.

“Like many scientists, as soon as I heard about the new coronavirus, I wanted to help and started to think about how my area of research might intersect with coronavirus research efforts,” said Bates, a professor of medicine. “I am fortunate to be at UofL, which is one of the few places in the country where we have the facilities to do experiments using the SARS-CoV-2 virus.”

Palmer, director of UofL’s Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases (CPM), conducted proof-of-concept experiments showing the aptamer was effective against the virus at doses previous research has shown to be safe in patients. Palmer also is working on another potential COVID-19 treatment, Q-Griffithsin, developed at UofL in partnership with the National Cancer Institute and the University of Pittsburgh.��

The CPM houses UofL’s Regional Biocontainment Laboratory, one of only 12 regional and two national biocontainment labs in the United States and the only one in Kentucky. Established with support from the NIH to conduct research with infectious agents, the lab includes Biosafety Level 3 facilities built to the most exacting federal safety and security standards. The stringently secure facilities protect researchers and the public from exposure to the pathogens being investigated.��

UofL is providing financial support for COVID-19 research, but additional funds are needed to continue the work over time. Donations specifically for the research .