Coronavirus/COVID-19 Research Programs
Matthias Schnell, MS, PhD
Dr. Schnell and his laboratory have extensive experience developing viral vaccines and diagnostics that they are using to target Covid-19. Specifically he is developing novel vaccines based on past success with targets identified in SARS and MERS. In addition the laboratory has a collaboration with the Department of Pathology (Steve Peiper) to develop an antibody test against SARS-CoV-2 to identify individuals recovered from the infection.
Gudrun Debes, DVM
COVID-19 can range from asymptomatic or mild course to a severe and fatal disease with acute respiratory distress syndrome. In severe cases, COVID-19 lung pathology is characterized by massive proteinaceous exudates with hyaline membrane formation, edema, and lymphocytic infiltrates. As both viral damage and overzealous adaptive immune responses can contribute to such pathology, we will analyze the quality of the pulmonary immune response related to different disease courses in patients. Specifically, we will analyze the affected respiratory tract in patients with different disease course for infiltrating leukocyte subsets and cytokine profiles of lymphocytes, as well as other parameters of pulmonary immune responses such as localized anti-viral antibody titers. The results will inform the type of pulmonary immune response that is beneficial versus detrimental in the infection with SARS-CoV2, thereby informing of novel therapeutic avenues.
“BiTE”ing Coronaviruses - Generation of Bi-specific T-cell Engaging Agents for Cellular Immunotherapy Against SARS-Cov2
Claudio Giraudo, PhD
Effective Immune responses against viral infections requires a strong engagement of competent T-cells in order to destroy virally-infected cells and clear the virus. My laboratory is focused in developing novel approaches to potentiate human T-cells responses against SARS-Cov2 by using Bi-specific T-cell Engaging agents (BiTEs) that prime T-cells and ultimately create immunity against these viruses. In particular we will evaluate combinations of different T-cell engaging molecules such as single chain antibodies (scFv) against CD3/ CD28/ LFA1 with SARS-CoV2 antigens to raise T-cell specific immune responses. These Bi-specific agents will be coupled to different nanoparticles and used to stimulates primary human T-cells from healthy controls and T-cell specific responses will be evaluated against engineered cell lines expressing viral proteins. Results from our studies will generate a new platform to investigate novel approaches to potentiates T-cell responses against viral infections and might provide insight into novel therapeutic interventions against SARS-CoV2.
Botond Igayrto, PhD
Dendritic cells (DCs) are professional antigen presenting immune cells that play important role in driving and controlling anti-pathogen immune responses. However, their specific roles in regulation of anti-SARS-CoV2 immune responses are unknown. In order to efficiently fight SARS-CoV2 and other coronavirus infections, we posit, that we must first understand the contribution of DCs in driving and regulating anti-SARS-CoV2 responses. Thus, here we aim to define the role of DC subsets in induction and regulation of anti-SARS-CoV2 responses, and test different vaccines platforms that best activate DCs to promote long-lasting immunity towards different coronaviruses.
Felix Kim, PhD
Sigma1 (also known as Sigma-1 receptor) is a unique cellular protein that was recently identified as a potential drug target to treat COVID-19. Dr. Felix Kim’s laboratory in the Department of Cancer Biology at Thomas Jefferson University has extensive experience in Sigma1 (Sigma-1 receptor) research and deep domain knowledge in Sigma1 biology and pharmacology. Dr. Kim and his team are currently working to:
- Establish a laboratory test to identify which Sigma-1 and -2 receptor targeted therapeutic agents will be effective in treating COVID and to understand how they work.
- Test Sigma-1 receptor targeting drugs in animal models of coronavirus infection to evaluate their efficacy in eliminating SARS-CoV.
Sangwon Kim, PhD
(in collaboration with Luis Sigal)
Infection of COVID-19 can occur to people who have been being treated with antibiotics due to previously-existing disease conditions, leading to the changes in their microbiota. However, we do not know how this antibiotic treatment-induced changes in microbiota affect our ability to fight against COVID-19. We will use humanized mouse models of COVID-19 infection and determine the role of microbiota in the pathogenesis of COVID-19.
Holly Ramage, PhD
My lab is interested in host-pathogen interactions and the mechanisms by which viruses are able to evade innate immune responses. To address the ongoing pandemic caused by SARS-CoV-2, we are working to better understand the biology of this virus and to develop tools to support future research. Currently, we are collaborating with Dr. Sara Cherry and the High Throughput Screening Core at the University of Pennsylvania to conduct large-scale screening of libraries of compounds, including FDA-approved drugs, which are able to inhibit SARS-CoV-2 replication. We hope to discover both direct-acting antivirals, as well as compounds that target cellular processes required for infection. We hope these studies lead to new therapeutic options during this epidemic. Our longer term goals are focused on deciphering cellular mechanisms that restrict SARS-CoV-2. These include cell intrinsic responses, such as nonsense-mediated decay, as well as regulation of innate immune signaling. These studies will elucidate the mechanisms by which the SARS-CoV-2 establishes infection and evades anti-viral defenses.
Luis J. Sigal, DVM, PhD
While useful for testing vaccines, current mouse models transgenic for human ACE2 do not reproduce the pathogenesis of SARS-COV-2 in humans. We are using i-GONAD technology to rapidly generate novel transgenic models with the expectation that they may be more suitable for pathogenesis studies.
Luis J. Sigal, DVM, PhD
Vaccines are extremely useful to prevent viral diseases. However, a major problem is that they must be tailored for each emerging pathogen and take a very long time to develop. Our laboratory has been working for many years to understand how the different components of innate immunity control susceptibility to lethal viral disease. Our goal is to learn how to harness the innate immune system not to prevent SARS-COV-2 infection but to make the infection much better controlled. Such an approach could reduce the severity and lethality of COVID19 disease while allowing for the natural development of immunity.
Evaluation Quality of SARS-CoV-2-specific CD8 T Cells in COVID19 Patients with Different Clinical Outcomes: A Key for Efficient & Long-lasting Immunity?
Yuri Sykulev, MD, PhD
It is well known that cytolytic CD8 T cells are critical for the elimination of virus-infected cells. The acute phase of SARS in humans is associated with a reduction in the number of T cells in the blood. It has been recently shown that the excessive exhaustion of CD8+ T cells are correlated better with severity of SARS-CoV-2 disease than age and chronic alignment. Moreover, memory T cell responses elicited against SARS-CoV-1 proteins were found to persist up to 11 years post-infection while the antibody response generated by the infection progressively decreased over time. Therefore, it is essential to establish criteria to characterize the efficiency of naturally occurring SARS-CoV-2-specific CD8 T cells response and to compare this with CD8 T cell response elicited during immunization (vaccination) in vivo. We have previously shown that kinetics of calcium accumulation in stimulated cytolytic CD8 T cells is linked to kinetics of granule release and kinetics of target cell destruction of target cells. Based on these findings, we have developed a novel assay, called CaFlux assay, that permit to estimate quality of cytotoxic T cells by quantifying their Ca2+ response. We are set up to apply our recently developed novel approach to identify antigens recognizable by SARS-CoV-2-specific T cells as well as efficiency of pathogen-induced T cells derived from human blood patients and uninfected people. These will help to elucidate criteria for protective CD8 T cell response against SARS-CoV-2 and provide a platform for evaluation and improvement of SARS-CoV-2 vaccine efficacy.