Infection of Immature Red Blood Cells May Help Explain Low Oxygen Levels in COVID-19 Patients

University of Alberta researchers discover that SARS-CoV-2 infects immature red blood cells, reduces oxygen in the blood and impairs the immune response.

A new study, published in the journal Stem Cell Reports by researchers at the University of Alberta, sheds light on why many COVID-19 patients, even those not in hospital, suffer from hypoxia — a potentially dangerous condition that involves is of reduced oxygenation in the body tissues. The study also shows why the anti-inflammatory drug dexamethasone has been an effective treatment for people with the virus.

“Low oxygen levels in the blood have been a major problem in COVID-19 patients,” said study leader Shokrollah Elahi, an associate professor in the Faculty of Medicine and Dentistry. “Therefore, we thought that a possible mechanism could be that COVID-19 affects red blood cell production.”

In the study, Elahi and his team examined the blood of 128 patients with COVID-19. The patients included those who were severely ill and admitted to the ICU, those with moderate symptoms and were hospitalized, and those who had a mild version of the disease and spent only a few hours in the hospital. The researchers found that as the disease became more severe, more immature red blood cells flowed into the circulation, sometimes as much as 60 percent of the total cells in the blood. In comparison, immature red blood cells make up less than one percent, or none at all, in a healthy person’s blood.

Shokrollah Elahi led new research that sheds light on why many COVID-19 patients have low oxygen levels in their blood and why the anti-inflammatory drug dexamethasone works to treat the potentially dangerous condition. Credit: University of Alberta

“Immature red blood cells are in the bone marrow, and we don’t normally see them in the circulation,” explains Elahi, who is also a member of the Women and Children’s Health Research Institute and the Cancer Research Institute of Northern Alberta. “This indicates that the virus is affecting the source of these cells. As a result, and to compensate for the depletion of healthy, immature red blood cells, the body makes significantly more to provide the body with adequate oxygen.”

Immature red blood cells susceptible to COVID-19

The problem is that immature red blood cells don’t carry oxygen – only mature red blood cells. The second problem is that immature red blood cells are highly susceptible to COVID-19 infection. Because immature red blood cells are attacked and destroyed by the virus, the body is unable to replace mature red blood cells — which only live for about 120 days — and its ability to carry oxygen in the bloodstream is reduced.

The question was how the virus infects the immature red blood cells. Elahi, known for his previous work showing that immature red blood cells made certain cells more susceptible to HIV, began by investigating whether the immature red blood cells have receptors for SARS-CoV-2. After a series of studies, Elahi’s team was the first in the world to show that immature red blood cells expressed the receptor ACE2 and a co-receptor, TMPRSS2, which allowed SARS-CoV-2 to infect them.

In collaboration with the lab of virologist Lorne Tyrrell of the U of A’s Li Ka Shing Institute of Virology, the team conducted investigative infection tests on immature red blood cells from COVID-19 patients and proved that these cells had become infected with the SARS -CoV-2 viruses.

“These findings are exciting, but also show two important implications,” Elahi said. “First, immature red blood cells are the cells that are infected by the virus, and when the virus kills them, it forces the body to try to meet its oxygenation requirements by pumping more immature red blood cells from the bone marrow. But that only creates but more targets for the virus.

“Second, immature red blood cells are actually potent immunosuppressive cells; they suppress the production of antibodies and they suppress the immunity of T cells against the virus, making the whole situation worse. So in this study we showed that more immature red blood cells mean a weaker immune response against the virus.”

The Dexamethasone Mechanism

After discovering that immature red blood cells have receptors that allow them to become infected with the coronavirus, Elahi’s team began testing several drugs to see if they could reduce the susceptibility of immature red blood cells to the virus.

“We tried the anti-inflammatory drug dexamethasone, which we knew helped reduce mortality and disease duration in COVID-19 patients, and we found a significant reduction in the infection of immature red blood cells,” Elahi said.

When the team started investigating why dexamethasone had such an effect, they found two possible mechanisms. First, dexamethasone suppresses the response of the ACE2 and TMPRSS2 receptors to SARS-CoV-2 in immature red blood cells, reducing the likelihood of infection. Second, dexamethasone increases the rate at which the immature red blood cells mature, causing the cells to shed their nuclei more quickly. Without the nuclei, the virus has nowhere to reproduce.

Fortunately, no significant changes in the way COVID-19 patients are now treated are needed to put Elahi’s findings into practice.

“Over the past year, dexamethasone has been widely used in the treatment of COVID-19, but there was no solid understanding of why or how it worked,” Elahi said. “So we’re not repurposing or introducing a new drug; we provide a mechanism that explains why patients benefit from the drug.”

Reference: “Erythroid Progenitors and Progenitors Suppress Adaptive Immunity and Are Invaded by SARS-CoV-2” By Shima Shahbaz, Lai Xu, Mohammed Osman, Wendy Sligl, Justin Shields, Michael Joyce, D. Lorne Tyrrell, Olaide Oyegbami, and Shokrollah Elahi, May 11, 2021, Stem Cell Reports.
DOI: 10.116/j.stemcr.2021.04.001

Elahi noted that Wendy Sligl and Mohammed Osman played a critical role in recruiting COVID-19 patients for the study. The research was supported by Fast Grants, the Canadian Institutes of Health Research, and a grant from the Li Ka Shing Institute of Virology.