Gene Expression Changes Could Be Behind Long-Haul COVID-19 Symptoms

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Sick woman with Long COVID lying in bed

Early-stage research from Texas Tech University Health Sciences Center suggests exposure to SARS-CoV-2 infection can result in long term changes to gene expression in human bronchial cells, which could be behind the many ‘long-haul’ COVID-19 cases now being observed.

Now we are more than a year into the pandemic there is a worrying trend of so called ‘long COVID’ cases where people are infected with the virus, but instead of recovering fully continue to have a range of symptoms including fatigue, low fever and cognitive dysfunction.

These cases don’t seem to be limited to people who experience severe COVID-19, but also occur in mild or even initially asymptomatic cases. Not everyone who is infected with SARS-CoV-2 develops long COVID—defined as ongoing symptoms for more than 2 months—and the exact nature of the condition and what causes it is still unclear.

To investigate this phenomenon, Nicholas Evans, a graduate student at Texas Tech University, and colleagues created a cell line model of COVID-19 to study genetic changes related to infection.

They used an air-liquid interface cell culture technique, where one side of the human primary bronchial epithelial cells is attached to media and the other side exposed to air, to simulate the inside of the lungs. The cells were exposed to recombinant spike protein from SARS-CoV-2 for several hours and then allowed time to ‘recover’ from the exposure for 48 hours.

Evans and team then analyzed gene expression in the cells to evaluate the impact of exposure to the spike protein.

“We found that exposure to the SARS-CoV-2 spike protein alone was enough to change baseline gene expression in airway cells,” said Evans who is based in the laboratory of Sharilyn Almodovar, Ph.D., at the Texas Tech University Health Sciences Center.

“This suggests that symptoms seen in patients may initially result from the spike protein interacting with the cells directly.”

The researchers analyzed expression in genes with functions related to oxidative and osmotic stress, cell death, the inflammatory response, and DNA damage, among others. They found that expression of CCL2, IL1A, IL1B, and MMP9 showed up to two-fold changes in expression after recovery.

All of these genes play a role in inflammation. CCL2 levels are increased in neuroinflammatory disorders such as epilepsy and Alzheimer’s, as well as in some autoimmune diseases like psoriasis, whereas MMP9 is needed for wound healing and recovery from lung damage.

IL1A and IL1B are part of the interleukin family of cytokines and directly produce inflammation and promote fever, as well as playing a regulatory role in the greater immune response.

Evans presented the results at the virtual Experimental Biology conference this week. While this work is preclinical and needs further validation, it provides an interesting insight into gene expression changes that could be behind some of the symptoms seen in long COVID cases.

Writing in the conference abstract, the authors conclude: “Our preliminary results suggest that the SARS-CoV-2 spike protein is enough to change the baseline protein expression in primary human primary bronchial epithelial cells. After recovery, genes related to immune response retained changes in gene expression, and these may indicate relevant long-term effects in asymptomatic patients.”

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