During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

“At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died,” said Jiapeng Huang, anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine.

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in .

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

This research is supported by the National Heart, Lung, And Blood Institute under award numbers R01HL158779 and R43HL169129 and the National Institute of Allergy and Infectious Diseases under award number R01AI172873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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.

UofL has been designated the first Center of Excellence by Pfizer Vaccines.

“UofL’s Division of Infectious Diseases has a rich history of collaboration with Pfizer through the successful implementation of numerous clinical epidemiological research studies. We are excited to formalize a long-term collaboration that builds on these past successes,” said Julio Ramirez, MD, chief of the Division of Infectious Diseases at the .

The Center of Excellence, directed by Ramirez, is a collaboration between the university and the pharmaceutical corporation aimed at determining the human health burden of important infectious diseases and potential vaccine effectiveness. The data will provide robust evidence to national health officials and independent policy makers who develop recommendations for the use of vaccines in immunization programs worldwide. Studies will take place in hospitals, long-term care facilities and the community.

UofL is the first Center of Excellence selected by Pfizer Vaccines Medical Development and Scientific/Clinical Affairs to be part of an international network of epidemiological research organizations. This designation is for a period of three years with an option for renewal. Pfizer selected UofL because of the university’s exceptional capabilities for conducting population-based surveillance and clinical research that engages multiple health care facilities, health care personnel, industry and communities-at-large.

“Pfizer has had an outstanding working relationship with the University of Louisville for more than 10 years,” said Luis Jodar, PhD, chief medical and scientific affairs officer, Pfizer Vaccines. “The quality of disease burden evidence varies widely worldwide. Deriving accurate and credible population-based incidence estimates require comprehensive surveillance to identify cases of diseases within a well-defined and well-characterized geographic area. Thanks to UofL’s excellent network of research partners, the population available for research studies in Louisville can provide the data to derive estimates of disease burden that can be generalized nationally.”

The demographics of Jefferson County, Kentucky, are similar to the United States in general, including racial and ethnic make-up, socioeconomic status, and the proportion of rural and urban populations.

The research studies conducted as part of the center may lead to economic growth and development for the city of Louisville and the Kentuckiana region, including jobs and educational opportunities in the health care industry.

“This collaboration will provide increased visibility for the university on a global scale, making UofL attractive for high-caliber researchers and research grants,” said Neeli Bendapudi, PhD, president of UofL. ”It also presents an exceptional opportunity for our researchers to improve the human condition by helping to reduce the burden of infectious diseases worldwide by generating data that will inform governments and health care policymakers.”

Pfizer studies anticipated for UofL include population-based surveillance of infectious diseases including Streptococcus pneumoniae, a bacteria which causes pneumonia and other infections, Clostridioides difficile, a bacteria that causes severe diarrhea and colitis, and respiratory syncytial virus (RSV), a common virus associated with mild cold-like symptoms but can cause severe infection in some people, including older adults. Visit for additional information on these diseases and two Center of Excellence studies already underway at UofL:

• The City of Louisville Diarrhea (CLOUD) study launched in September 2019. Pfizer will be providing up to $6.5 million in funding for a one-year study of the incidence of diarrhea among Louisville-area residents.
• The Louisville Pneumonia study is up to $4.5 million in funding provided by Pfizer for a one-year study of the incidence of pneumonia among adults in Louisville that launched in November 2019.

Check out the video for more information: 

Espinosa and several colleagues at the UofL School of Medicine conducted a retrospective study of 61 patients treated using a standardized approach of video-assisted thoracoscopic surgery (VATS) and IV antibiotics administered in the hospital, with transition to broad-spectrum oral antibiotics about five days after surgery or when the patients were discharged. The study showed a 92-percent rate of recovery without complications using this approach, which is comparable to that achieved with prolonged courses of IV antibiotics continued at home, but avoids potential complications associated with home IVs.

“Given the adverse effects of IV antibiotics and the potential possible complications of PICC lines, transitioning to oral antibiotics and providing a shorter course than previously advised is a good strategy,” Espinosa said. “The outcomes appear to be good even when cultures are negative and the choice of antibiotic is an empiric one.”

The children in the study, all previously healthy children with community-acquired bacterial pneumonia and empyema, were admitted to Kosair Children’s Hospital from 2008 to 2012. All of the children were treated with prompt VATS and early transition to oral antibiotics, which continued for an average of two weeks after discharge.

“Many physicians believe that placing a chest tube and giving fibrinolytics is better than VATS for treatment of empyema,” Espinosa said. “In this study, we show good outcomes, short length of stay, minimal complications and short course of antibiotics for pediatric patients with empyema who underwent VATS.”