Jefferson Researchers Take On the Coronavirus

CORAVAX – Jefferson’s vaccine against COVID-19

By building upon on an existing safe and effective vaccine, one with already well-established and currently active manufacturing hubs, one which could be made to store on the shelf until it’s reconstituted with water, researchers at the Jefferson Vaccine Center have a COVID-19 vaccine candidate that could cover a global need. Read more about the vaccine here.

Engaging Key Components of the Immune System – T-Cells – in Developing Immunotherapy Against the Coronavirus

Conventional vaccines against viruses like the novel coronavirus or SARS-CoV2, can sometimes trigger an undesired widespread inflammatory response, rather than the selective destruction of the virus. T-cells, which are a type of white blood cell, are critical in targeting our immune systems to a pathogen. We have different T-cells in our body, each designed to fight off one type of pathogen. Claudio Giraudo, PhD, Associate Professor of Microbiology and Immunology, and researchers in his laboratory are trying to develop immunity against SARS-CoV2 by facilitating a T-cell response against the virus, using a novel approach called Bi-specific T-cell Engaging agents (BiTEs).

BiTES have been used in cancer to prime T-cells to recognize and attack certain types of cancer cells. In the same way, Dr. Giraudo and his lab are looking to engineer T-cells that would be able to recognize proteins expressed on the SARS-CoV2 virus. The approach would help the immune system mount a stronger, and more directed response to destroy cells that have been infected by the virus.

Understanding the Role of Dendritic Cells – The Initiators of the Immune Response

In order for immune cells to respond to an invading pathogen like SARS-CoV2, they must first recognize a specific type of marker or antigen that is expressed on the virus. Dendritic cells, named for their tree-like branches, capture viruses and present their antigens to other immune cells such as T and B cells, activating them. The T-cells can then begin to attack the virus-infected cells and clear them from the body, while the B cells start producing proteins called antibodies to neutralize the circulating viruses. In a way, dendritic cells initiate a cascade of immune responses. However, it is unclear what specific role dendritic cells play in regulating the immune response to the novel coronavirus. Botond Igyártó, PhD, Assistant Professor of Microbiology, and his laboratory will be conducting research to define the role of different types of dendritic cells in the immune response against SARS-CoV2. They also aim to test different vaccine candidates to see which one best activates dendritic cells to promote long-lasting immunity towards different coronaviruses.

Learning to Strengthen Immunological First Responders and Developing Better Models

Creating protective antibodies will be the goal of any COVID-19 vaccine. But it takes time for our bodies to ramp up antibody production. It can be from 4-5 days to upwards of a week or two. In the meantime, the virus continues to replicate in our bodies, infecting new cells, and new organs.  Luis Sigal, PhD,  Professor of Microbiology and Immunology, is looking at the our immune system’s first responders, called the innate immune system, which are usually first to the scene of infection and start taking action immediately – well before the specialists – the antibody-producing cells – are ready. Dr. Sigal’s team will investigate what the different cells of this first-responder immunity are doing in COVID-19, in the hopes of reducing disease severity.

Dr. Sigal’s team (in collaboration with Dr. Sangwon Kim) is also working on developing better models to study COVID-19 late-stage disease. Although current animal models show similar rates of infection, they don’t exhibit the same severity of disease as human hosts, so we still don’t have a very clear picture of what causes such a severe and deadly reaction in humans.

To learn more about antibodies and antibody testing, watch the animated illustration below:

Targeting a Target of the Coronavirus – the Sigma-1 Receptor

Viruses can’t live, grow, and propagate on their own. Instead, they hijack the machinery inside the cells of an infected host, and use it to multiply and make more viral proteins to reproduce in a process called replication. An important part of that cellular machinery is Sigma1 (also known as sigma-1 receptor), a protein that helps regulate the production, processing, and quality control of essential proteins and lipids that a cell needs, especially under conditions of stress. It was discovered recently that Sigma1 interacts with an essential protein involved in SARS-CoV2 virus replication called NSP6, leading researchers to speculate that Sigma1 could be a potential drug target – perhaps disrupting its role inside cells could prevent SARS-CoV2 from co-opting the cellular machinery.

However, other than this very recent discovery, nothing is known about the interaction between coronaviruses and the Sigma1 protein. Dr. Felix Kim’s laboratory in the Department of Cancer Biology has extensively studied Sigma1, its biology and pharmacology, or how it interacts with different drugs and chemicals. Dr. Kim and his team are currently studying different drugs that target Sigma1 and how they work. They are also testing these drugs in preclinical or animal models of coronavirus infection to see if they are effective in combating the virus.

Bacteria vs. Viruses: What Role Does our Microbiota Play?

The human microbiota – all of the bacteria living in and on our bodies that are vital for human health – often play an important role in preventing infection by viruses and bacteria that harm our health. Our normal microbiota often helps protect us from disease-causing pathogens. Sangwon Kim, PhD, Assistant Professor of Microbiology and Immunology (in collaboration with Dr. Luis Sigal), will study what role natural microbiota play in COVID-19, from infection to severe disease.

Testing the Immunology of Severe COVID-19 Disease

As the coronavirus disease grows in severity in some people, the immune reaction rages in the lung tissue, and other organs infected by the virus. Researchers have noticed that in really severe cases of the illness, the numbers of a certain immune cells drop. Depletion of these cells, called CTLs (cytolytic CD8 T cells), is more predictive of poor outcomes than even older age or the presence of other diseases. CTL are capable of recognizing and destroying virally infected cells before the virus expresses all proteins necessary to make a new viral particle. This allows the CTLs to stop viral spread in its tracks. Yuri Sykulev, PhD, Professor of Microbiology and Immunology, is developing a novel test to study these cells in order to understand their role in severe COVID-19 disease. Researchers recently found that the level of T cells, including CTLs in COVID-19-infected people is significantly decreased. The reason for decrease during COVID-19 infection is not clear yet. If having large numbers of these cells is confirmed as an essential component of a life-saving immune reaction, such a test could help ensure that vaccines against SARS-CoV-2 also activate CTLs and help keep their numbers strong.

Screening for New Drugs Against Coronavirus

The mechanisms by which viruses are able to escape innate immune responses, those immunological first responders, can be complex. The lab of Holly Ramage, PhD, Assistant Professor of Microbiology and Immunology aims to understand the biology of SARS-CoV2 and to develop tools to support future research. She is collaborating with Sara Cherry, PhD at the University of Pennsylvania to conduct large-scale high-throughput screening of libraries of compounds, including FDA-approved drugs, which are able to inhibit SARS-CoV2 replication. The researchers hope to discover both direct-acting antivirals, as well as compounds that target cellular processes required for infection.  The hope is that these studies lead to new therapeutic options during this epidemic.  Longer-term goals are focused on deciphering cellular mechanisms that restrict SARS-CoV2 infections. These studies will help researchers understand how SARS-CoV2 establishes infection and evades anti-viral defenses.

Studying the immune response in the lungs of COVID-19 patients as the disease progresses

COVID-19 can cause a range of breathing problems, from a mild dry cough to shortness of breath and in the most severe cases, respiratory failure. Virus particles enter our body through the mucous membranes that line the nose, mouth, and eyes. They can then multiply and travel down our throat and into our respiratory tract. As our body tries to fight off the infection, our airways and lungs can become irritated and inflamed. In more severe cases, the inflammation can reach both lungs, and the lungs start to swell and fill with fluid and debris from immune cells. There are many different types of immune cells and it’s unclear which ones are entering the lungs. Researchers led by Gudrun Debes, PhD, Assistant Professor in Microbiology and Immunology is collaborating with Michael Stephen, MD, in the Department of Medicine, Division of Pulmonary and Critical Care to study the types of immune cells and molecules entering the lungs at different points in the disease progression. Their findings will inform what types of immune cells are helpful in fighting off the disease, and which may exacerbate symptoms by producing an overzealous immune response. The more we know about how people react to this virus, the better we’ll be able to create therapies to fight it.