Steven Rowe, M.D., professor in the Division of Pulmonary, Allergy, and Critical Care and director of the Cystic Fibrosis Research Center, is working to develop animal models of COVID-19, something he has pioneered for cystic fibrosis in his project “A Ferret Model of COVID-19 Pathogenesis and Treatment."

Rowe’s study pursued the hypothesis that the SARS-CoV-2 infection could cause mucociliary dysfunction through the involvement of ciliated respiratory cells, and this could be modeled in certain animals to show severity. His work has shown that mucociliary dysfunction is in fact happening in animal models and may contribute to secondary infections observed in COVID-19.

Rowe says his laboratory has developed a method to monitor ciliated cell function in volunteers with COVID-19, are presently enrolling acutely ill patients, and seek to extend this to patients with sustained lung problems. If successful, this research could explain why some patients have sustained problems with respiratory infections.

Additionally, through studying animal models and cigarette smoke, he was able to observe smoking increased ACE2 expression, the functional receptor for SARS-CoV-2.

Based on preliminary data, Rowe received an additional competitive supplement to the R35 grant to pursue work in animal models.

Success in animal models has led to additional studies in humans with COVID-19.

Yulia Khodneva, M.D., internal medicine specialist in the Division of Infectious Diseases, sought to conduct an observational study of patients with laboratory-confirmed COVID-19 infection. Khodneva’s goal was to ascertain whether their baseline use of RAAS inhibitor agents were associated with worse health outcomes of the COVID-19 infection such as a need for Intensive Care Unit (ICU) admission, acute respiratory failure requiring intubation and mechanical ventilation, and mortality.

Khodneva found that the use of RAAS inhibitors was associated with decreased in-hospital mortality from COVID-19 in a racially diverse patient sample. The use of RAAS inhibitors were not associated with ICU-level care or hospital readmissions in the cohort of patients with COVID-19, whereas patients with diabetes were at a higher risk for the same-hospital readmission. Among patients with hypertension, baseline RAAS inhibitor use was associated with a reduced risk of invasive mechanical ventilation. Her finding support continued RAAS inhibitor use during the pandemic.

The results of her study have been presented to Center for Clinical and Population Research and she was invited to present to the Center for Outcomes and Effectiveness Research and Education meeting, focusing on COVID-19-related research.

Randall Davis, M.D., professor in the Division of Hematology and Oncology, says his team’s overall studies have been focused on lymphocyte developmental regulation and its relationship to B cell malignancies and disease states.

“During the onset of the pandemic, I was concerned that many of my patients who have B cell chronic lymphocytic leukemia (CLL) and are immune compromised would be at great risk from the complications of COVID-19. Thus my laboratory adapted to the situation by developing an assay capable of detecting a potential correlate of immune protection.”

Davis explains that characterizing and quantitating antibodies capable of blocking entry of the virus—via interactions between the spike protein and the ACE2 receptor—enabled multiple collaborations with colleagues internally in infectious disease, pathology/blood bank, radiology, pulmonology, and other areas, as well as with virologists/microbiologists and immunologists outside of UAB.

“With this assay we have been able to actively screen convalescent plasma to ensure the presence of high-titer neutralizing antibodies for infusion into patients with COVID-19 at UAB.”

More recently, Davis’s team has been examining this parameter in vaccine recipients. “We are learning about the timing of antibody responses to RNA vaccines, the capacity to respond, and the durability of these antibodies.”

Davis says that his team has accomplished many of the goals that they originally set forth with the emergency funds. “We expect this foray will yield additional future returns.”

Plus, Davis notes that what regulates the variability in responses and the B cell origins of these antibodies requires further scrutiny and investigation. “As a result of these studies, we have applied for external funding to maintain this work and redirect it back to our overall long term goals on lymphocyte developmental regulation.”

Through the Urgent COVID-19 Clinical Research and Laboratory Research Fund, Benjamin Larimer, Ph.D., assistant professor in the Department of Radiology, received funding for his project, “Development of a Rapid and Scalable COVID-19 Antibody Epitope Mapping Platform by Phage Display.” His COVID-19 research looked to expand potential impact by utilizing an existing technology.

On the study, he says his group used a tool previously employed for cancer studies. “It has significantly expanded the impact we can have by looking at biomarkers in a variety of new ways.”

The project resulted in new findings on how the immune system makes antibodies in patients, which led to a new antibody test that could provide an inexpensive, but quick way to track immunity. Larimer says his team is fortunate to have been accurate in projecting outcomes for the study.

“Our work resulted in a new patent being filed, and a UAB startup: P3 Diagnostics,” Larimer explains. “While the startup is still in its early stages, we hope that it will allow for translation of discoveries at UAB to make it into clinical applications.”

Larimer and his team have presented the study’s results to local, regional, national and international news outlets and industry meetings, which has greatly increased exposure for the excellence in research at UAB. 

Troy Randall, Ph.D., professor in the Division of Immunology and Rheumatology, chose collaboration for his project, “Development of SARS-2 Recombinant Proteins for Diagnostics, Vaccine Testing and Research.” Randall served as the lead principal investigator on the study and worked jointly with four other labs, including labs of Drs. Lund, Green, King, and Rosenberg.

Fran Lund, Ph.D., explains that the project was designed to build a cytometric bead array (CBA) that would allow the team to detect antibodies specific for different coronaviruses in the blood, lung, nose, and saliva of individuals (or animal models) that were previously infected with SARS-CoV-2, as well as those who had received the COVID-19 vaccine.

“We built a platform that allows for high throughput screening for these antibodies from hundreds of samples at a time. This CBA platform will allow us to determine whether particular kinds of immune responses to the infection or vaccination are associated with particular types of disease (e.g. mild or severe) or with individuals who might have other co-morbidities (e.g. diabetes) that may affect their ability to respond to the virus or vaccine,” Lund says.

The team was able to build the CBA platform, and it works even better than they had originally envisioned. Lund says, “Importantly, working with our informatics colleague, Dr. Alex Rosenberg, we have automated the analysis portion of the process which greatly increases our capacity to analyze large numbers of samples.”

The original project has led to additional funding and additional studies. The CBA platform is used in pharmaceutical company sponsored pre-clinical studies of vaccine responses in animals that are receiving different types of COVID-19 vaccines, which are being delivered via different routes (e.g. intranasal route). The platform is also used in NIH studies to examine whether infection and vaccination generate different types of immunity to SARS-CoV-2.

W. Winn Chatham, M.D., professor in the Department of Medicine and Lous W Heck Clinical Scholar in Rheumatology, says his project, “Early Identification and Treatment of Cytokine Storm Syndrome in COVID-19,” took precedence over his other research, and essentially halted his other scholarly activities in 2020.

Chatham’s study focused on cytokine syndrome in COVID-19 positive patients, and was the first randomized placebo controlled trial of anakinra use in COVID-19 conducted in the U.S. “The premise and aims of the trial sensitized UAB providers to hyper-inflammation associated with COVID-19, and helped to effect incorporation of assessments for such in the standard initial assessments of patients admitted with COVID-19,” he says.

The projected outcome of Chatham’s study was that treatment with anakinra would resolve COVID-19 associated hype-inflammation and decrease the need to escalate oxygen supplementation requirements in admitted patients. Chatham says this projection was not the case on a background of steroid treatment—one that had become standard care when the trial was able to enroll the first patient.

“We also predicted that that patients admitted with severe complications of COVID-19 would have biomarkers consistent with those we have observed in other cytokine storm syndromes; what we found was that this was rarely the case. COVID-19 induces hyper-inflammation that is unique. We did predict that there would be genetic risk factors for COVID-19 hyper-inflammation, and the preliminary genetic studies appear to confirm this,” he says.

Chatham’s whole genome sequencing studies yielded results that provided preliminary data for additional studies, which confirm the prevalence of these mutations in a larger cohort of COVID-19 patients and patients with other infection-triggered hyper-inflammation syndromes. The study was a foundation for additional studies seeking to determine the functional correlates of identified mutations.

To study immune responses in COVID-19 patients, Paul Goepfert, M.D., professor in the Division of Infectious Diseases, created a biospecimen repository with his Urgent COVID-19 Clinical Research and Laboratory Research grant.

Goepfert says that in the lab, “We study T cell responses that are induced following COVID-19 infection or vaccination and have stored samples from over 800 patients from which to undertake these studies.”

Early on, Goepfert’s goal was to enroll 100 patients, and now, his team has far exceeded that number. “Multiple investigators throughout UAB are utilizing the data and samples obtained from the COVID-19 Biorepository,” he says. “This will eventually lead to grant funding that will help support faculty, staff, and infrastructure at UAB.”

The future of the biorepository looks promising, as funding from multiple investigators is in pending status, and numerous projects are ongoing. Plus, “Several investigators are on a patent for a monoclonal antibody to treat COVID-19. This product is being developed as a possible inhaled therapy for COVID-19 patients,” Goepfert says.

Nicholas Lennemann, Ph.D., assistant professor in the Department of Microbiology, aimed to develop and characterize a fluorescent CoV infection reporter, and identify antivirals in relevant mouse models using the reporter, with his grant from the Urgent COVID-19 Clinical Research and Laboratory Research Fund.

Lennemann’s team has continued to develop an infection reporter that streamlines infection assays in the bio-safety level 3 lab (BSL3). Unlike enteroviruses, CoV replicates in association with the ER membrane, as do flaviviruses. Lennemann made modifications to an existing enterovirus reporter in parallel for CoV and flaviviruses to determine if reporters can be developed for viruses that replicate at the ER.

They found that substitution of the PVR TM domain in the initial construct for the TfR TM domain and a flavivirus protease cleavage site allowed for flavivirus cleavage; however, introduction of 10 different CoV protease recognition sites (PLpro or 3CLpro) did not yield a functional reporter.

Interestingly, the team included this site for both SARS-CoV2 and OC43 in the reporters previously and did not observe cleavage by OC43 or 3CLpro expression, suggesting protease recognition is more complex.

The future of his research includes modifying the split fluorescent GFP reporter to include Sec61B TM and several viral protease recognition sites to determine if they are recognized by SARS-CoV2 and/or OC43. These are useful tools for work in the BSL3, but also for understanding the molecular determinants of CoV protease recognition/cleavage.

Sue Feldman, Ph.D., associate professor in the School of Health Professions and School of Medicine, says her project, “HelpBeatCovid19: Crowdsourced COVID-19 Symptom Tracker,” helped build great collaborations across campus.

HelpBeatCOVID19 helps public health officials and health care workers track symptoms before COVID-19 spreads by encouraging people to take a daily survey about their symptoms. The symptom tracker provides up-to-date information that tracks the progression of symptoms in communities in real time.

“When this project was started, things were moving way too fast to think about outcomes,” says Feldman. “The immediate goal was to keep exposures away and prevent the disease from spreading.”

For Feldman, this project furthers her research on building information systems for social good. For her and other collaborators at UAB, this project helped develop great collaborations across campus, ones that otherwise would take years.

This initial funding was only the beginning as it led to $7.1 million in CARES Act funding.

Feldman goes onto say while this wasn’t your typical bench science discovery, it provided a sense of comfort for K-12 and higher education students and families as students and employees were coming back to and remaining on campus.

 Jessy Deshane, Ph.D., associate professor in the Division of Pulmonary, Allergy, and Critical Care, has been interested in chronic lung disease and environmental exposure for years.

“I have focused my research program on asthma and lung cancer, both are impacted by these exposures. To delineate the underlying molecular mechanisms and spatial resolution of immune responses in these diseases, we developed perfused three dimensional human lung tissue models that recapitulate the tissue architecture and the microenvironment, Deshane says.

As the COVID pandemic evolved, her team was able to quickly adapt these models for human COVID-19 infection. They were also able to quickly investigate SARS CoV-2 immune responses and candidate therapeutics to attenuate SARS-CoV-2 infection and reinvigorate exhausted T cells.

The team predicted that the models would be of high utility for evaluation of fibrotic events that result from long term chronic inflammation associated with COVID-19.

“As optimal animal models are still being developed for SARS CoV-2 infection, our perfused human tissue models have opened doors for investigations of long term consequences of chronic inflammation due to COVID-19,” Deshane says.

The three dimensional perfusion human lung tissue models can be used to model SARS CoV-2 infection and to evaluate anti-viral therapeutics and local immune responses.

The team has submitted more grant applications, and is currently evaluating novel lines of investigations of sphingolipid metabolism that are influenced by COVID-19. 

Ahmed Zaky, M.D., MPH, professor in the Department of Anesthesiology and Perioperative Medicine, was the principal investigator on the study, “Inhalational Bitter Taste Receptors Agonists for the Treatment of SARS-COV-2,” which also worked with Kevin Harrod, Ph.D., and Dan Berkowitz, M.D.

Their project goal was to determine whether BTRAs (Q, HQ, PTU) reduce SARS-COV-2 replication in-vitro. Cells were divided into treatment and pre-treatment groups depending on whether viral infection occurs prior to BTRAs (treatment group) or after (pre-treatment) viral infection. Then, viral replication was assessed using polymerase chain reaction assays.

Of the tested compunds, only HCQ and QS showed antiviral activity.

Zaky is currently testing more BTRAs. BTRAs with antivrial activity are being tested in human cell cultures. Moreover the team is working on inhalational formulation of BTRAs with antiviral activity in vitro.

Sixto Leal, M.D., Ph.D., assistant professor in the Department of Pathology, is involved in over 15 projects focused on COVID-19 infection due to the funding of his pilot project, “Optimization of SARS-CoV-2 Diagnostic Testing Throughput and Prognostic Significance.”

“Close collaboration with CCTS sequencing and bioinformatics experts during this pilot program has enabled us to identify prognostic markers in original diagnostic respiratory sample (AIM2),” he says.

This collaboration also led Leal’s team identifying one of the first UK variant strains (B.1.1.7) in Alabama and, now, they are working together to establish a statewide COVID-19 genome sequencing network to identify variants of public health significance.

AIM1 of his Urgent COVID-19 Clinical Research and Laboratory Research grant led to the $30 million CARES Act GuideSafe™ initiative, which is largely responsible for enabling a safe return to college campuses. It also enabled diagnostic testing expansion at UAB, facilitating resumption of UAB Hospital operations, campus sentinel testing, and rapid development of a diagnostic tests that detect both SARS-CoV-2 and Influenza.

On his work, Leal says, “This work identified a correlation between disease severity and IFN beta and RANTES protein levels in nasal swab samples taken at the time of initial diagnosis. Confirmation at the RNA level is ongoing and may enable future incorporation into RT-PCR diagnostic tests.”

AIM2 helped establish the State of AL COVID-19 sequencing network. “AIM2 is still ongoing but has significant potential for incorporation of prognostic markers, like IFN beta, into diagnostic tests informing medical decisions based on the likelihood of progression to severe disease.”

Because of studies stemming from this pilot award, Leal aims to submit a K08 proposal on COVID secondary infections.

Kevin Harrod, Ph.D., Benjamin Monroe Carraway Endowed Chair and professor in the Department of Anesthesiology and Perioperative Medicine, is no stranger to SARS viruses. A scientist who has focused his entire career on studying respiratory and emerging infectious disease, he says that COVID-19 was a culmination of all he had learned in his previous studies. In the face of a global crisis, Harrod was able to act urgently.

“The award allowed my laboratory to get started immediately without the concern of finding funding.”

“As the only laboratory in the School of Medicine with experience working on coronaviruses—from my studies of the first SARS pandemic in 2002-2003—we were able to go back to our research protocols and quickly identify the methodologies and protocols for handling the SARS-CoV-2 virus,” Harrod explains.

Along with Justin Roth and other key compliance and safety staff, Harrod is largely responsible for onboarding scientists in UAB’s SEBLAB, including bio-safety level 3 labs.

For the funded study, his team initially set up a small drug screening platform, then were able to identify FDA drugs that could be repurposed as antivirals for COVID-19 therapy. “We continue to work in this area and continue to identify new antivirals.”

Harrod’s team was recently awarded a grant from the Cystic Fibrosis Foundation, which allowed his team to study SARS-CoV-2 virus in the setting of cystic fibrosis. Harrod says that, interestingly, one of the cystic fibrosis drugs may have antiviral activity.

Now, Harrod’s team has found about 18 drugs that have antiviral activity against SARS-CoV-2. “Many of these will be lead compounds in our drug discovery endeavors for the next year,” he says.

Chad Petit, Ph.D., associate professor in the Department of Biochemistry and Molecular Genetics, says his project allowed him to build the ground work for expanding his lab’s focus to include host pathogen interactions involving coronaviruses.

“The funding gave me the opportunity to obtain preliminary data and develop reagents for future grant opportunities,” he says.

“Our lab was the first to solve the high-resolution structure of SARS-CoV-2 nsp1, a protein that plays a vital role in the coronavirus lifecycle,” Petit says. “Nsp1 has been highlighted as a potential target for future drug discovery efforts and the development of live attenuated viral vaccines. In this study, we compared the nsp1 from SARS-CoV-2 and SARS-CoV-1 to determine how much of the protein structure was conserved between these two closely related viruses.”

Petit and his team published the results and analysis in Journal of Virology. “Our artwork, based on our findings, was selected for the cover of the issue that our article was published in.”

Now, Petit is developing a reverse genetics system to generate mutant SARS-CoV-2 viruses. This will allow him to interrogate how any interactions his team observes affect the CoV replication cycle.