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UAMS Team Leads the Quest to Understand Long COVID
At the Forefront:
UAMS Search for Answers to Long COVID-19 Yields Possible Cause
By David Robinson
Within months of COVID-19’s arrival, its list of disturbing health effects grew to include longlasting fatigue, brain fog and other debilitating symptoms. Known today as long COVID-19 or long-haul COVID-19, it has disrupted education plans, careers, and the basic activities of life.
The global search for answers recently yielded a possible cause at the University of Arkansas for Medical Sciences (UAMS), drawing national attention and hope for those with long COVID-19.
Leading the research is John Arthur, M.D., Ph.D., a UAMS nephrologist who has treated kidney failures caused by the virus, SARS-CoV-2. Through his research, he learned that a protein known as ACE2 plays a key role in the body’s immune response to coronavirus. Arthur has long studied ACE2 because of its role in kidney function.
“I was really inspired to begin this COVID-19 research because I was already familiar ACE2, which just so happens to be the protein that the coronavirus hijacks to get into cells,” Arthur said.
SARS CoV-2 attaches to the ACE2, and once inside a cell the virus commandeers the molecular machinery and multiplies.
He moved quickly in 2020 to conduct research into ACE2’s role in coronavirus infections. That work led to the recent groundbreaking discovery of rogue antibodies that appear weeks after an initial COVID-19 infection. The discovery
could lead to new treatments, possibly with existing drugs, Arthur said.
“This all came together very nicely thanks to great support from our institutional leaders and a team with remarkable immunology expertise,” said Arthur, a professor in the College of Medicine Department of Internal Medicine and associate director of the UAMS Translational Research Institute.
Arthur’s work and other signature COVID-19 research at UAMS has been supported by Laura James, M.D., director of the Translational Research Institute, and Shuk-Mei Ho, Ph.D., Vice Chancellor for Research and Innovation. Ho provided pilot funding to jump-start Arthur’s COVID-19 research in 2020, and James helped him quickly assemble the team needed to conduct the longCOVID-19 study starting in early 2021.
CONNECTING THE DOTS
A talented interdisciplinary team has been crucial to Arthur’s ability to advance the research, he said.
Arthur knew that the normal function of ACE2 (angiotensin-converting enzyme 2) is to metabolize a peptide that activates the immune system. He was also aware that an acute infection causes a decrease in ACE2, and that ACE2 begins to function normally again during the typical two-to-three-week recovery period.
But for those with long COVID-19, it appeared to Arthur that the normal activity of ACE2 was continuing to be suppressed, interfering with the body’s immune response. What could be causing it?
“I couldn’t come up with an answer, but I knew who to ask,” Arthur said.
He contacted Terry Harville, M.D., Ph.D., a professor in the UAMS College of Medicine Department of Pathology and Department of Internal Medicine, and medical director of the Histocompatibility and Immunogenetics Laboratories.
“Whenever I have a complicated immunology question, I call Terry,” Arthur said. “I told him what I knew and where I was stumped, and it took him about 10 seconds to come up with the answer.”
The two settled on the hypothesis that, in people with long COVID, the antibodies created to attack the virus begin producing autoantibodies that attack the ACE2. The autoantibodies attach to the ACE2 and disrupt its work, a possible cause of long COVID-19.
“Even though the COVID infection may resolve, the autoantibodies may result in a wide range of longCOVID-19 symptoms,” Harville said.
UAMS researchers Terry Harville, M.D., Ph.D. and John Arthur, M.D., Ph.D. (pictured here) lend their combined expertise, along with other key members of a multidisciplinary team to discover if autoantibodies are the true culprits in long COVID-19.
FINDING THE ROGUE ANTIBODIES
Arthur then turned to a UAMS immunology team that had developed a high-accuracy antibody test in 2020 for SARS-CoV-2. That test was a key part of a statewide antibody survey supported by Arkansas Governor Asa Hutchinson and other state leaders.
For Arthur’s study, an antibody test was developed by researchers Craig Forrest, Ph.D., professor; Karl Boehme, Ph.D., associate professor; and Shana Owens, Ph.D., post-doctoral fellow, in the College of Medicine Department of Microbiology and Immunology.
This is true team science.
The team’s work led to the first known discovery of rogue antibodies against the ACE2.
Forrest recalls that he, Boehme, and Owens had less than two weeks to develop the test to meet a funding application deadline.
They were “swinging for the fences,” Forrest said, but he was skeptical there would be autoantibodies against the ACE2 because there is so little precedent for it. He got a surprise when he reviewed the first lab results.
“I was totally shocked, and I texted Karl, ‘Holy cow, we may actually have something here,’” he said. “Although I thought it wouldn't work, I also thought it was 100% worth giving it a try because it's a really compelling hypothesis.”
Josh Kennedy, M.D., who worked with Boehme and Forrest on the 2020 antibody test, is also a collaborator on Arthur’s project. Kennedy is a clinical researcher at Arkansas Children’s Research Institute and associate professor in the Department of Pediatrics, Division of Allergy and Immunology.
The team tested de-identified blood samples for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. In 81% of patients with a history of COVID-19, the samples had the antibodies that attacked the ACE2.
In participants with no history of COVID-19, no autoantibodies were created to attack the ACE2 enzyme.
“ACE2 is critical in the body for helping to regulate the level of inflammation,” Harville said. “So if there’s disruption of this function, it increases inflammation in the body. Our research indicates that this may be one of the reasons why people with COVID-19 continue to have debilitating symptoms.”
“Everything that we’ve found is consistent with these autoantibodies as the instigators of long COVID, so it’s an exciting development that merits further study,” Arthur said. The team’s findings were published in September in the journal The Public Library of Science ONE (PLOS ONE). Since then, Arthur has been bombarded with emails and phone calls from across the U.S. Most are from people experiencing long COVID-19 who are desperate for answers.
“I receive a lot of correspondence from people who are suffering, and the stories are heartbreaking,” Arthur said. “One was from a medical student who had to give up his dream because he was so severely fatigued and depressed that he just could not go on. I had another from a university professor who had to resign.”
WHAT’S NEXT
Arthur is moving his research into the next phase, inviting people to participate. His goal is to determine if there is an association between the long COVID-19 symptoms and the rogue autoantibodies.
“We're focusing on fatigue because that’s a primary symptom, and we're hoping to be able to recruit people from all over the country,” Arthur said. “This will give us a fuller picture and answer some key questions that we couldn’t in our first study, which was limited to de-identified clinical data.”
Arthur and UAMS are steering potential study volunteers to a website created by the Translational Research Institute. The website, ARresearch.org, includes a registry with checkboxes for interested volunteers to include their research and health interests. The registry was recently updated to include checkboxes for COVID-19 and Long Haul COVID-19.
“Our team will be contacting people in the registry to ask if they would like to participate in this study,” Arthur said.
“If our next steps confirm that these antibodies are the cause of long COVID-19 symptoms, there are medications that should work to treat them. If we get to that phase of research, the next step would be to test these drugs and hopefully relieve people of the symptoms they're having.”
The multidisciplinary team also includes College of Medicine researchers Christian Herzog, Ph.D., in the Department of Internal Medicine, and Juan Liu, M.D., Ph.D., from the Department of Pathology.
“This is true team science,” Arthur said. “We put together a great group of investigators that had never worked together to produce these very exciting results.”
David Robinson is the Communications Manager for the Translational Research Institute of the University of Arkansas for Medical Sciences.
