College of

What makes some COVID-19 cases deadly?

September 14, 2020

As the coronavirus spread around the globe, Jeremy Prokop wondered why it causes relatively mild symptoms in some patients while it is deadly for others.

“In a subset of patients – and we really don’t know why yet – they start to get heart failure, kidney failure, and their systems start shutting down,” he said. “One of our areas of interest was in finding out what makes COVID-19 so much more severe than other coronaviruses. This has been the big challenge with COVID.”

To find out why, Prokop, PhD, assistant professor, teamed up with other researchers, including several College of Human Medicine students, to study how the virus invades and interacts with human cells. Their work resulted in three published studies identifying key proteins made by the virus and genetic variants in some patients that make it much more deadly.

“One of the things I’d like to highlight is the incredible research some of our students have been doing with Spectrum Health,” said Prokop, who is appointed to the college’s departments of Pediatrics and Human Development, and Pharmacology and Toxicology.

The first study, published in May in the journal Physiol Genomics, centered on a previously healthy 16-year-old admitted to Helen DeVos Children’s Hospital with a common virus called Epstein-Barr. Although many people infected with Epstein-Barr have no symptoms, some develop mononucleosis. In this patient, the infection led to multiple organ failure, a life-threatening condition sometimes called a cytokine storm.

The study, co-authored by Surender Rajasekaran, MD, an assistant professor at MSU and a pediatric intensivist at the children's hospital, identified a rare genetic variant in the patient that allowed the virus to hijack her cells, causing her immune system to become overactive and leading to multiple organ failure. She was successfully treated with drugs that lowered her immune response, the same drugs now being used in severe COVID cases.

The same principle applies to how COVID-19 invades and spreads in some patients, causing their immune systems to become overactive, Prokop said. Understanding exactly how was the goal of a second study published in the Journal of Biological Chemistry.

For that study, several students gathered information on the characteristics of 24 proteins produced by the coronavirus and ran computer simulated models to analyze how each protein acted within human cells. One protein called spike on the surface of the virus binds with a protein in human cells called ACE2, allowing the virus to invade the cells, where it replicates and spreads.

The researchers found variations in ACE2, including among African Americans, which could explain why a disproportionate number of them have died from the disease.

Another protein called NSP6 appears to help the virus move around.

A third study, published in the Journal of Proteome, focused on the nucleocapsid protein, or Protein N, in COVID-19. Normal human cells recognize the genetic material called RNA in an invading virus and destroy it, preventing the virus from replicating. Protein N stops the human cells from destroying the virus’s RNA, allowing it to replicate, the study found.

A combination of genetic variants and environmental factors, including pre-existing conditions, likely accounts for why some COVID patients become seriously ill, Prokop said.

“That combination of genetic and environmental variants is what we think puts so many people at risk,” he said.

Identifying which patients have those variants could allow physicians to begin treatment earlier and prevent them from becoming seriously ill.

“When patients come in with COVID, we’re trying to identify any genetic traits that might make them have a more-severe response,” said Austin Frisch, a second-year College of Human Medicine student who worked on one of the studies. “That could dictate what kind of treatment they get.”