Harvard Researchers Uncover Causes of Hyperinflammation Accompanying Severe Covid

A research team led by Harvard scientists discovered triggers for the hyperinflammation accompanying severe Covid-19 cases in a study published in Nature on April 6.

Scientists at Harvard Medical School and Boston Children’s Hospital collaborated to produce the findings, which revealed connections between infected immune cells, respiratory problems, and organ damage.

Judy Lieberman ’69, a co-author of the study and HMS professor, said no prior research had explored the link between inflammation and Covid-19.

“It’s well recognized that inflammation, and something called cytokine storm — which is an extreme form of inflammation — is at the root of severe Covid, but nobody knows how it got triggered, or why,” Lieberman said.

The study found that Covid-19 infects monocytes and macrophages, white blood cells that respond to infection by identifying antibodies surrounding the virus and, afterward, taking up the virus — a process that results in programmed cell death, or pyroptosis.

Pyroptosis releases inflammatory molecules that are linked with organ failure and excessive blood clotting, especially among older patients or patients with comorbidities.

Caroline Junqueira, an HMS researcher who co-authored the study said these bodily responses could best be characterized as “immunopathology,” in which the body “becomes the disease itself.”

Junqueira added that despite the negative effects of pyroptosis, it can still be a protective mechanism through warding off viral replication because it is faster than the replication process.

“Cell death is really fast,” she said. “It’s much faster than virus life cycles.”

Although not every viral infection leads to pyroptosis, pyroptosis in Covid-19-infected cells is a “dead end for the virus,” according to Junqueira.

Junqueira added that future studies could tackle the relationship between immune response and Long Covid, in which symptoms persist long after infection.

“[Long Covid] is a persistent inflammation — a systemic inflammation,” Junqueira said. “What we are planning to do now is to try to understand if [these] inflammatory monocytes are actually playing a major role.”

Lieberman added that the study could be important for designing future Covid-19 treatments.

“People designing both vaccines and antibody therapies should really consider not only whether the antibodies block or neutralize infection, but they should also consider the other functional properties of the antibody,” Lieberman said.

These “functional properties” could inform decisions about Covid-19 health policy and therapy going forward, Lieberman said.

“People have to really understand the science and what’s known, and keep working to understand more in order to devise the best therapies and not be prejudiced without understanding the data,” she said.