RECOVER pathobiology studies look inside the body to learn more about Long COVID

As part of RECOVER’s portfolio of Long COVID research, investigators are conducting a type of research known as pathobiology studies. In these studies, specialists called pathobiologists look inside the bodies of people experiencing Long COVID. 

By examining small amounts of tissue, blood, and saliva—known as biosamples—pathobiologists can see what is happening in internal organs (like the lungs or brain) and even in individual cells within those organs. What they observe can help them better understand the processes in the body that can lead to the development of Long COVID. 

“As we continue to study Long COVID, the results coming out of the first round of studies are finding the pathways of the condition are more and more complex,” said Dr. Christine Bevc, pathobiology study manager at RECOVER’s Administrative Coordinating Center. “So each study is uncovering more to understand the answers to important questions like ‘What causes Long COVID? Why do some get it and others don’t? How can we treat it and address it?’”

By expanding our understanding of which pathways contribute to which Long COVID symptoms, pathobiology studies are bringing researchers closer to answering these questions.

Biosamples are vital to RECOVER pathobiology studies 

RECOVER’s research could not move forward without the contributions of people who have volunteered to participate in its studies. So far, RECOVER study participants (adults, children, pregnant women, and people taking part in the tissue pathology [autopsy] study) have shared more than 1 million of the biospecimens that are critical to RECOVER’s pathobiology research. 

Pathobiologists look at these biosamples under a microscope and may apply chemicals, such as colored stains, to make specific cells or parts of cells easier to see. Making these cells more visible helps pathobiologists evaluate processes happening inside the body. 

These processes, also known as biological mechanisms, occur when cells react or parts of cells interact in a certain way, resulting in a change in the body. Although some changes are noticeable because they take the form of a specific physical response (like shortness of breath), other changes are not as noticeable. These changes include those affecting how cells and parts of cells (such as proteins) help the body fight off infection or regulate important functions like smell and taste. These changes are too small to detect without the help of medical laboratory equipment. Learning more about biological mechanisms enables RECOVER researchers to answer different types of questions about Long COVID that observational and electronic health record (EHR) studies are not designed to answer. 

In addition to studying biosamples from humans, some pathobiologists search for insights about the human body by studying how animals and microorganisms like bacteria (called model organisms) react to a condition. These model organisms—which include mice, fruit flies, and yeast—serve as a model for the human body because they have biological characteristics, called genes, that are similar to human genes. Model organisms also often reproduce quickly, meaning that scientists can more easily study the long-term effects of a health condition on a large population in a laboratory setting. These factors allow scientists to safely apply what they learn from experiments on model organisms to human beings. 

RECOVER pathobiology studies take a comprehensive approach 

Since 2022, RECOVER has awarded funding to over 60 different pathobiology studies. These studies cover a wide range of Long COVID symptoms, including heart problems, breathing difficulties, sleep disturbances, loss of smell and taste, and brain fog (difficulty thinking or concentrating). RECOVER’s pathobiology studies focus on understanding the biological mechanisms that could be associated with these symptoms. 

Bevc explained that each of these 60 studies takes a unique approach to further our understanding of Long COVID. “There’s no duplication of effort,” she said. “Every pathobiologist is coming at Long COVID from a different perspective and applying different methods. We’re surrounding Long COVID and examining it from every angle.”

RECOVER’s pathobiology research has 3 main goals: 

1. Identify biological mechanisms. RECOVER researchers are studying the root causes of Long COVID by looking at how cells or parts of cells interact in the body. These interactions may help explain why Long COVID symptoms develop and how they affect different people.
2. Identify organ systems affected by biological mechanisms. Different biological mechanisms impact different parts of the body, and researchers are studying how these mechanisms lead to a wide range of Long COVID symptoms.
3. Produce results that can later be re-created by other studies. RECOVER researchers are working to identify signs in the body that can be measured in the same way across different studies. This scientific approach ensures that results from one study can be repeated by others. When multiple studies reach similar findings, scientists can be sure that their results are accurate. 

RECOVER pathobiologists focus on the most promising biological mechanisms 

Although early investigations have ruled out some mechanisms, promising leads continue to emerge. Currently, RECOVER pathobiologists are studying a group of mechanisms that includes:

• Autoantibodies. Antibodies are cells the body produces to fight off infection and disease. Autoantibodies are antibodies that mistakenly attack the body’s own healthy cells and proteins. Some patients with Long COVID have higher levels of autoantibodies, which may cause swelling (inflammation) and damage to body tissues.
• Neutrophils. White blood cells help the immune system fight infections and heal wounds. Neutrophils are the most common type of white blood cells. Some people with Long COVID have a higher number of neutrophils in their blood counts, and some patients have neutrophils with unusual shapes. Researchers are investigating the link between neutrophils and Long COVID symptoms such as lung scarring (pulmonary fibrosis), heart and blood vessel issues, and problems with the brain and nervous system.
• Microclots. Microclots are small blood clots that occur in small blood vessels. Microclots normally break down after a couple of weeks, but researchers have found that microclots remain in some Long COVID patients. These persistent microclots can damage blood vessels and block tissues and organs from getting the oxygen they need.
• Viral reservoirs. In some people, a virus or parts of a virus can remain in the body even after a person seems to have recovered from the initial phase of the disease the virus causes. The areas of the body where these viruses or parts of viruses remain are called viral reservoirs. Viruses in these reservoirs can continue making copies of themselves, or they can remain inactive (dormant) only to be reactivated later by another infection. Researchers are investigating how viral reservoirs might affect the body’s immune system, damage organs, and trigger Long COVID. 

Findings from pathobiology studies can have multiple applications 

The RECOVER pathobiology studies are giving researchers an inside look at how COVID-19 affects different people’s bodies at a cellular level—insights that are essential to advancing our understanding of the root causes of Long COVID. As pathobiologists learn more about the biological mechanisms that contribute to Long COVID, they hope that their findings can support treatment and prevention of the condition. 

For example, the presence of some biological mechanisms may help in confirming that someone has Long COVID. Even people who show no symptoms or only a few mild symptoms may still have developed Long COVID. 

Biological mechanisms can also play an important role in Long COVID clinical trials and the search for treatments that can help manage the condition’s symptoms. As pathobiologists conduct more studies, they learn more about the biological mechanisms that contribute to specific Long COVID symptoms. This knowledge can inform future clinical trials and could even support the design of treatments targeting the sources of specific Long COVID symptoms. By studying these mechanisms before and after treatment, researchers can also gain a better understanding of how effective the treatment might be.

As pathobiology studies progress, they could lay the groundwork for more accurate diagnostics and targeted treatments. You can explore the 60+ pathobiology research projects funded by RECOVER and dive into the published findings from this growing body of research. 

 “What’s exciting looking ahead is that we’re starting to see some connections in the findings, and RECOVER just made more data available to support this work,” Bevc said. “These data will be available to researchers outside of RECOVER through BioData Catalyst® to help make the data as widely accessible as possible.” 

Subscribe to the RECOVER Report below to stay tuned for the future stories in this series, where we’ll discuss the findings from individual pathobiology studies and explore what they might suggest about the root causes of Long COVID’s lasting symptoms.