1. Lisa Cassis, PhD
UK College of Medicine
Sex Differences in COVID-19
There is emerging evidence that compared to women infected with SARS-CoV-2 coronavirus have more severe disease and higher mortality than men. Angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is downregulated on the cell surface following viral entry. ACE2 also suppresses the renin-angiotensin system (RAS), important in lung and cardiovascular function. The location of ACE2 on the X chromosome and its positive regulation by estrogen suggests females are protected from an over-active RAS following virus infection. We will administer the Spike protein portion of SARS-CoV-2 to cells and experimental male and female mice to examine sex differences in ACE2.
2. Rebecca Dutch, PhD
UK College of Medicine
SARS-COV-2 Spike Protein Stability and Fusion Activity: Roles of Proteolytic Processing and Key Residues
The SARS-CoV-2 Spike (S) protein is essential for viral entry into host cells and subsequent infection. The S protein is a class I viral fusion protein, as are fusion proteins from multiple other viruses. Building on expertise developed over 20 years on the synthesis, post-translational modifications, cellular trafficking and membrane fusion function of class I viral fusion proteins, we aim to decipher the role of S proteolytic processing and of specific S residues in S protein post-translational processing, stability, and membrane fusion function both in human cells, and in cells from the putative bat reservoir host.
3. Beth Garvy, PhD
UK College of Medicine
Longitudinal Study of Immune Responses in CoVID-19 Patients
COVID-19 emerged due to a novel coronavirus to which people had no immunity. The world-wide pandemic will only go away when sufficient numbers of individuals are immune to the virus. This requires exposure of individuals to the virus or development of a vaccine. The goal of this project is to understand the long-term effects of the virus on the immune system. Specifically, we will examine the antibody response, T cell response, and immune cell interactions with the coagulation system over the period of 6 months with the goal of understanding how long immunity lasts after infection with the virus.
4. Joel Hamm, MD, MPH
UK College of Medicine
STINCKY: Smell Testing for Infection with Novel Coronavirus in Kentucky
The Smell Testing for Infection with Novel Coronavirus in Kentucky (STINCKY) Study will test how useful a smell test is in determining who may have COVID-19. Loss of smell and taste have been reported as the most frequent symptoms of COVID-19. In our study, we will test patients with and without COVID-19 with a 4 item pocket smell test (PST) to determine who has lost their sense of smell. This PST may be useful in the future as a screening test and our study hopes to identify how good it is at screening for COVID-19.
5. Konstantin Korotkov, PhD
UK College of Medicine
Inhibitors of Papain-like Protease from SARS-CoV-2
Most of the current therapeutic treatment options are based on the empirical use of approved antiviral and antiparasitic drugs, an inefficient strategy as illustrated by a number of terminated clinical trials. A more focused strategy would deploy the repurposed approved drugs for other indications. Currently, the reported repurposing efforts have been focused on main protease (Mpro) of SARS-CoV-25 [bioRxiv 033233]. Another key protein in coronaviral replication is the papain-like protease (PLpro). Not only does it play a role in processing the nonstructural proteins (Nsps) 1-3 that arise from cleavage of the polyproteins ppla and pplab, PLpro is a critical modulator of the host innate immune response. The deubiquitinase activity of PLpro 6-10 interferes with phosphorylation of interferon-regulatory factor 3 (IRF3), preventing nuclear import, and ultimately blocking the production of type-I interferons.10,11 SARS-CoV PLpro has also been found to interferes with interferon-stimulated gene products (IGS) by removing ISG15 units from labeled proteins8 and the nuclear factor kB pathway.9 Thus disruption of PLpro activity will not only block Nsps processing but allow the host innate immune response to more readily detect and clear the virus. We believe that PLpro represents a highly promising, underexplored target for drug repurposing. While the crystal structure of SARS-CoV-2 PLpro has been recently reported (PDB ID 6W9C), it displays a non-physiological trimer, which distorts the substrate-binding site. Therefore, a reliable in silico screening for PLpro inhibitors is challenging. Thus, our strategy will rely on in vitro screening of approved drugs and drug-like compounds, rather than computational approaches.
6. Charles Lutz, MD, PhD
UK College of Medicine
Hypoxia-Induced Dysfunction of Virus-and Fibrosis-Fighting Human NK Cells-A Proposed Cure
Natural killer (NK) lymphocyte defender cells rapidly respond to virus infection by killing infected lung cells and limiting virus spread. NK lymphocytes also produce large amounts of interferon-γ, which stops the virus from making more copies of itself. NK lymphocytes and interferon-γ prevent fibrosis, which thickens the lungs. We propose that some individuals poorly control the COVID-19 virus and develop lung fibrosis because of weak NK lymphocytes. We found that NK lymphocytes are damaged by low oxygen level (hypoxia), which is found in COVID-19 patients. We will investigate how hypoxia disarms NK lymphocytes and test drugs that protect NK lymphocytes.
7. Peter Nagy, PhD
UK College of Agriculture, Food and Environment
Identification of Cellular Targets of Human SARS-COV2 in Yeast
SARS-CoV-2 is a global threat by causing COVID-19 disease in humans. SARS-CoV-2 replicates inside the host cells and exploits host factors. The PI’s aim is to identify host factors and cellular targets, which are essential for SARS-CoV-2 – host interactions during infection. Identifying the cellular targets of SARS-CoV-2, followed by gaining insights into molecular mechanisms of coronavirus-host interaction will likely open up targets for antiviral interference with SARS-CoV-2 replication and its ability to cause disease in humans. The PI will use a powerful tombusvirus-yeast “cellular biosensor” system invented and developed in his lab to identify cellular targets of viral proteins. Altogether, the current proposal could have major contributions to many areas of COVID-19 by unraveling new interactions for SARS-CoV-2 proteins with the host components.
8. Oleg Tsodikov, PhD
UK College of Pharmacy
Development of Ebselen/Ebsulfur Inhibitors of SARS-CoV-2 Main Protease Mpro for COVID-19 Therapy
The coronavirus main protease Mpro performs an essential function in the life cycle of SARS-CoV-2, the causative agent of COVID-19, by cleaving the viral polyprotein to form a functional RNA polymerase needed for viral replication. Mpro has been validated as a target of inhibitors that have antiviral activity in cell-based viral replication and plaque reduction assays. A potent and selective inhibitor of Mpro active in vivo would be highly desirable as a candidate for preclinical and clinical development as a COVID-19 therapy. This project will use rational medicinal chemistry and structural biology to develop novel inhibitors of Mpro against COVID-19.
9. Jill Turner, PhD
UK College of Pharmacy
CNS Involvement in the Progression of COVID-19: Preclinical Intervention with NMDA Receptor Antagonists
Though little is known currently about the CNS involvement in SARS-CoV-2 (CoV-2) infection, SARS-CoV-1 is neuro-invasive and has been found in the CSF of patients with neurologic demyelinating disorders, such as multiple sclerosis. Of note, CoV-2 (COVID-19) infected patients present with symptoms attributable to the CNS, i.e., loss of smell/taste, headache, and seizures. While these effects suggest direct CNS disruption, the mechanism is unknown. In this project, we are investigating whether the CNS manifestations of CoV-2 are due to primary neuronal infection or due to the secondary effects of pro-inflammatory cytokine secretion, driving massive neuroinflammation and demyelination. Furthermore, this project will test clinically-approved compounds targeting these CNS processes. These studies will address primary symptoms of CoV-2 infection, but also inform future studies assessing the long-term CNS effects of prior CoV-2 infection.
10. Jeremy Wood, PhD
UK College of Medicine
Dissecting the Underlying Mechanisms of Hemostatic Dysregulation in COVID-19 Patients
Data thus far has demonstrated an increase in clot formation/degradation and this change is even more striking in non-survivors of COVID19 infection. This data suggests a dysregulation of COVID19 patient’s hemostatic system is contributing to increased mortality. The goal of this study is to identify which components of the coagulation system are affected. The study will use a detailed measurements of platelet activation from COVID + and - blood samples, as well as several clinical data points such as prothrombin time, activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer, fibrinogen degradation products (FDP), antithrombin activity (AT), thrombin-antithrombin complex, platelet counts, and mean platelet volume.
