Pilot grants launch new research projects to fight COVID-19 pandemic
August 24, 2020
By Kristi Birch
With support from the University of Kansas School of Medicine and the vice chancellor for research at the University of Kansas Medical Center, four investigators have launched new research projects designed to help fight the COVID-19 pandemic.
Pilot grants of $50,000 have been awarded to the following faculty:
- Maria Kalamvoki, Ph.D., and Edward Stephens, Ph.D., who as a research team are determining how three of the novel coronavirus's membrane proteins affect the development of the disease. This knowledge could be used to inform vaccine development.
- Sarah Finocchario Kessler, Ph.D., MPH, who is designing an efficient, customizable contact-tracing system to control spread of the virus.
- Mary A. Markiewicz, Ph.D., who is investigating a way to ramp up the body's immune system to fight the disease.
These awards come on the heels of pilot grants for new COVID-19 research awarded earlier this summer by Frontiers: University of Kansas Clinical and Translational Science Institute.
The office of the Vice Chancellor for Research and the KU School of Medicine wanted to expand the opportunities those awards made possible and help translate more research discoveries into actual treatments and diagnostic tools that can help patients.
"This pandemic is a landmark moment for public health and those who have devoted their lives to medical science," said Matthias Salathe, M.D., interim vice chancellor for research at KU Medical Center. "We are responding by helping launch this new research with these awards, which will also increase the likelihood that these scientists will able to secure external funding to further their work."
Moreover, "providing this kind of seed funding helps launch new research that can be used not only for this particular virus, but also helps prepare us for future pandemics," said Akinlolu Ojo, M.D., Ph.D., MBA, executive dean of the KU School of Medicine.
When a virus infects a cell in the human body, its goal is to replicate itself and spread. Infected cells fight back by activating their immune responses to thwart the virus's ability to multiply. But viruses can be clever, and the smartest and most successful in causing diseases have figured out how to block or alter the immune responses of the cells they invade. Fatality rates indicate that the SARS-CoV-2 coronavirus, which causes COVID-19, thwarts infected cells' defenses better than the coronaviruses that cause the common cold, for example.
And sometimes, as also happens in some cases of the novel coronavirus, particularly when patients are elderly or immunocompromised, the cells' immune response becomes a double-edged sword: It goes into overdrive and leads to excessive inflammation, such as in the form of a "cytokine storm," which can cause cell death, tissue damage and ultimately end the patient's life.
Edward Stephens and Maria Kalamvoki want to understand how the SARS-CoV-2 virus handles the immune reaction of different kinds of human cells. For their pilot COVID-19 project, they are launching the first study of how three of the novel coronavirus's membrane proteins (E, S and M), which are believed to be the key determinants of how successful this virus is in causing disease, affect the body's immune response.
"Each of these proteins has properties that can initiate potentially anti-viral effects, or block or modulate these anti-viral effects," said Stephens.
In addition to researching how these three proteins act on host cells' immune responses, they will study the virus-like particles that are produced by these proteins to see how they affect the host cell and if they can counteract its anti-viral activity. And they'll look at different cell types found in the lung, such as fibroblasts and epithelial cells, to determine how they vary in their ability to launch anti-viral responses when infected.
Their work uncovering the biology of these proteins could form the basis of treatments for and prevention of COVID-19. "The outcome of our study will be to better understand pathogenesis [of the virus], and then be able to understand how this is going to impact the body's response to a vaccine, for example," said Kalamvoki.
Sarah Finocchario Kessler, Ph.D., MPH
Department of Family Medicine and Community Health
KU School of Medicine
As coronavirus cases have continued to increase, the United States has not had adequate staff or systems to track the contacts of each new person infected. Yet contact tracing is an essential infection containment strategy, especially when a vaccine or effective treatment is not available.
Contact tracers identify and notify anyone who has been in close contact with someone infected with the virus. They also can advise them on how to isolate and quarantine, get tested and monitor themselves for symptoms. When contact tracing works best, tracers also follow up with people about their health status while collecting data that enable health officials to look at disease trends and allocate resources accordingly.
But in Kansas, many county health departments lack an efficient, standardized system for contacting and following up with sick and exposed people. The result is that many who have the virus and those they have exposed receive just a single phone contact from a contact tracer. And without an efficient contact tracing system, making just those initial calls is a massive amount of work for a health department. Without a comprehensive system, health departments improvise to piece together data-collection tools for various components of case investigation, contact tracing and case resolution, which leads to inefficiencies and duplication of data entry.
"These awards provide our investigators with opportunities to move quickly toward developing research programs aimed at COVID-19 mitigation and treatment."
—Peter Smith, Ph.D., senior associate vice chancellor for research, KU School of Medicine
"Right now, given the huge influx in positive cases, it's very difficult to keep up with contact tracing," said Sarah Kessler. "By the time we reach people, they've likely already exposed anyone around them because they haven't received the information necessary to mitigate the spread."
Kessler wants to work with local health departments to change that. For her COVID-19 pilot project, she's creating a web-based, customizable system to improve contact tracing in Kansas and generate epidemiological data for the state. The basis of the COVID-19 Tracking System (CTS) is a system Kessler developed to diagnose and track babies exposed to HIV infection in Kenya, which has proved effective in expediting test results and connecting infants with treatment.
Users of the CTS will be able to collect data in real time, utilize a texting feature for follow-up customized for the person's preferred language and generate aggregated data to map performance. Without such a system, for example, generating a list of people who've been notified that they've been exposed but have not yet been tested can involve hours of cross-referencing reports from multiple systems. The CTS will contain customized algorithms and allow users to pull up such a list instantly. The tracer can then follow up with people about getting tested and identify obstacles to testing, such as transportation or language barriers, so the county can address them.
After developing the CTS, a main objective is to sync the CTS with the state's EpiTrax disease reporting system to further streamline efforts. The CTS will be piloted in Wyandotte and Johnson counties. If all goes well, the goal is to implement it across Kansas.
Mary A. Markiewicz, Ph.D.
Department of Microbiology, Molecular Genetics & Immunology
KU School of Medicine
Mary Markiewicz studies powerful immune system warriors known as T cells and natural killer (NK) cells. Types of white blood cells, T cells and natural killers seek and destroy abnormal or damaged cells, including tumor cells and those that have been infected by viruses.
Markiewicz is especially interested in a certain receptor expressed on T cells and NK cells known as NKG2D. This receptor, which activates these cells and sends them into battle, is particularly important in fighting tumors.
For her COVID-19 pilot research project, Markiewicz is going to switch gears and investigate the ability of that receptor to launch a fight against SARS-CoV-2, the virus that causes COVID-19. "We have preliminary data showing that a particular type of T cell can control the spread of this virus from one cell to another," she said. "And this T cell expresses the NKG2D receptor, which is the particular receptor my lab studies on other T cells and NK cells."
The Markiewicz lab's work will examine if NKG2D signaling activates that particular T cell type in response to SARS-CoV-2, and if increases in that signaling ramp up the ability of these T cells to fight the virus.
She will also be looking to see if the cells infected with the coronavirus express the proteins that are needed for these T cells to recognize them through the NKG2D receptor. "And then if the virus does induce those proteins, we want to find out if it's sneaky and also has ways of stopping their production, like some sneaky viruses do," she said.
If her work reveals a significant contribution of NKG2D to the control of SARS-CoV-2 by these T cells in the lab, Markiewicz would explore working with the Frontiers Clinical and Translation Science Institute to test methods of enhancing NKG2D signaling in COVID-19 patients to increase the function of these T cells to fight the virus.
These methods include using drug compounds that previously have been shown to increase NKG2D ligand expression on tumor cells; Markiewicz is testing them to see if they increase NKG2D ligand expression on SARS-CoV-2-infected cells. If so, that would warrant further testing of these drugs for their power to bolster the body's immune defense against COVID-19.