How Coronavirus Damages Lung Cells Within Mere Hours – And What Drugs Could Halt COVID-19 Infection

A team of Boston University researchers—hailing from BU’s National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BU’s Medical Campus, and BU’s Center for Network Systems Biology (CNSB)—embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cell–derived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.

The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.

Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, it’s expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.

“What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection,” says Elke Mühlberger, one of the study’s senior investigators and a virologist at BU’s NEIDL. She typically works with some of the world’s most lethal viruses like Ebola and Marburg.

“The most striking aspect is how many molecular pathways are impacted by the virus,” says Andrew Emili, another of the study’s senior investigators, and the director of BU’s CNSB, which specializes in proteomics and deep sequencing of molecular interactions. “The virus does wholesale remodeling of the lung cells—it’s amazing the degree to which the virus commandeers the cells it infects.”

Viruses can’t replicate themselves because they lack the molecular machinery for manufacturing proteins—that’s why they rely on infecting cells to hijack the cells’ internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells’ metabolic processes, Emili says, and even damages the cells’ nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, “cells infected with the deadly Ebola virus don’t show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact,” Mühlberger says.

The nuclear membrane surrounds the nucleus, which holds the majority of a cell’s genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cells—which normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathe—die. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.

“I couldn’t have predicted a lot of these pathways, most of them were news to me,” says Andrew Wilson, one of the study’s senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BU’s teaching hospital. At BMC, Boston’s safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospital’s ICU. “That’s why our [experimental] model is so valuable.”