How Coronavirus Damages Lung Cells Within Just Hours – And Which Drugs Can Stop COVID-19 Infection

Human lung cells infected with SARS-CoV-2 (red) (blue). Courtesy of Hekman et al. Credit: Courtesy of Hekman et al.

A multifaceted BU research team has discovered 18 FDA-approved drugs that can stop coronavirus infection early.

What if scientists knew exactly what would affect them? SARS-CoV-2 Was the virus in our lung cells within the first few hours of infection? Can they use that information to find drugs that interfere with the virus’s replication process before the virus has fully progressed? The finding that some existing FDA-approved drugs, including those originally designed to fight cancer, can stop the coronavirus in its orbit shows that the answer is certainly yes.

Boston University’s team of researchers are from BU’s National Emerging Infectious Diseases Research Institute (NEIDL), BU’s Medical Campus Regenerative Medicine Center (CReM), and BU’s Network Systems Biology Center (CNSB). Started for a month. A collaborative and interdisciplinary exploration that begins answering these questions by combining multiple disciplines in virology, stem cell-derived lung tissue engineering, and deep molecular sequencing. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus and tracked exactly what was happening in all of these cells in the first few seconds after infection. As if it wasn’t complicated enough, the team needed to cool the entire high-containment laboratory within NEIDL to an active 61 degrees Celsius. Fahrenheit..

What are the consequences of that challenging and large-scale business? The BU team has unveiled the most comprehensive map of all molecular activity to date in lung cells at the onset of coronavirus infection.They also found that there were at least 18 existing FDA-approved drugs that could be reused to fight. COVID-19 An infectious disease immediately after a person is infected. Experimentally, five of these drugs reduced coronavirus, which spreads to human lung cells, by more than 90%.Their findings are recent Molecular cell..

Researchers say that academic and industry collaborators around the world are now in contact with the team on the next steps to move findings from the bench to the bedside. (Although the COVID-19 vaccine has begun to be deployed, it is expected that it will take most of the year for a sufficient number of people to be vaccinated to generate herd immunity, and current vaccine preparations. There is no guarantee that will be as effective in the future. SARS-CoV-2 strains may emerge over time.) A more effective and timely therapeutic intervention is COVID- 19 May help reduce the total number of infection-related deaths.

“What makes this study unusual is that it looked at a very early point in time. [of infection]Only one hour after the virus infects lung cells. It was scary to see the virus already start damaging cells very early in the infection, “says Elke Mühlberger, one of the senior researchers in the study and BU’s NEIDL virologist. .. She usually deals with some of the world’s most deadly viruses, such as Ebola and Marburg.

“The most striking aspect is the number of molecular pathways affected by the virus,” said another senior researcher in the study, CNSB director of BU, who specializes in deep sequencing of proteomics and molecular interactions. One Andrew Emili said. “The virus performs extensive remodeling of lung cells. The extent to which the virus directs infected cells is amazing.”

Viruses are unable to replicate themselves because they lack the molecular mechanisms for producing proteins. As a result, the virus infects cells, hijacks the cell’s internal mechanisms, and uses it to spread its own genetic material. When SARS-CoV-2 takes over, the metabolic process of the cell is completely altered and can even damage the nuclear envelope of the cell within 3-6 hours after infection, which was surprising to the team. In contrast, “cells infected with the deadly Ebola virus show no apparent structural changes in the early stages of these infections, and the nuclear envelope remains intact in the later stages of infection,” says Mühlberger. ..

The nuclear envelope surrounds the nucleus, which retains most of the cell’s genetic information and controls and regulates normal cell function. When the cell nucleus is compromised by SARS-CoV-2, the condition of the entire cell deteriorates rapidly. Under siege, cells that normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide generated during respiration die. When cells die, they also emit pain signals that promote inflammation, accelerating cell death and eventually causing a cascade of biological activities that can lead to pneumonia, acute respiratory distress, and lung failure.

“I couldn’t predict many of these pathways. Most of them were news for me,” said one of the senior authors of the study, a CReM scientist, and the Boston Medical Center (BMC). Andrew Wilson, a pulmonologist, said. hospital. At BMC, Boston’s Safety Net Hospital, Wilson has been at the forefront of the COVID-19 pandemic since March 2020, seeking to treat and rescue the most ill patients in the hospital’s ICU. “That’s our reason [] The model is very valuable. “

“Science is the answer. When you use science to ask what goes wrong when lung cells are infected with the coronavirus, the cells tell us.”
— Darrell Cotton

The team leveraged CReM’s organoid expertise to grow human lung air sac cells, a type of cell that lines the lungs. Air sac cells are usually difficult to grow and maintain in traditional cultures and are difficult to extract directly from patients for research purposes. As a result, many coronavirus studies to date by other laboratories have relied on the use of more readily available cell types, such as monkey kidney cells. The problem with this is that monkey kidney cells do not respond to coronavirus infections like human lung cells, making them a poor model for studying the virus. What we learn from monkeys is not easily translated into clinically relevant findings. To treat human patients.

“Our organoids developed by our CReM faculty are made from stem cells, which are not the same as the living respiratory cells in our body, but are the closest to it,” the study said. Darrell Cotton, one of the seniors in the world, says. Author. He is the director of CReM, a pulmonologist at BMC, and has worked with Wilson in the ICU treating patients with COVID-19. The two frequently collaborated with Mühlberger, Emily, and other members of the research team through Zoom Call, who managed to join during a short tranquility in the ICU.

In another recent study using CReM-manipulated human lung cells, the researchers confirmed that the existing drugs remdesivir and camostat were effective in combating the virus, both of which were COVID-19. Is not the perfect solution to control the inflammation caused by. Remdesivir, a widely used antiviral drug, is already clinically used in patients with coronavirus. However, based on the discovery of new research that the virus causes serious damage to cells and causes inflammation within hours, researchers have found that after the infection has progressed until someone needs it, antivirals like remdesivir He says he’s unlikely to be able to take medicine. Wear a ventilator on the ICU. “”[Giving remdesivir] If the disease is already advanced, it cannot save lives, “says Emily.

Seeing how SARS-CoV-2 skillfully directs human cells and destroys them to perform a manufacturing operation that replicates the viral genome, it reminds researchers of another deadly intruder. I did.

“I was surprised that there are so many similarities between cancer cells and SARS-CoV-2 infected cells,” says Mühlberger. As part of their research, the team screened a number of anticancer drugs and found that some of them could block the growth of SARS-CoV-2. Like a virus, cancer cells want to replicate their genome and divide over and over again. To do this, it is necessary to mass-produce pyrimidines, which are the basic components of genetic material. Disrupting the production of pyrimidines with anticancer drugs designed for that purpose also blocks the construction of the SARS-CoV-2 genome. However, Mühlberger warns that anticancer drugs usually have many side effects. “Do we really want to use that heavy one against viruses?” She says. Further research is needed to weigh the strengths and weaknesses of such an approach.

The results of their latest research have spent four senior researchers and scientists, postdoctoral fellows, and graduate students in the lab completing their research almost 24 hours a day for almost four months. Very important for team leaders is to ensure that the setup has a solid foundation to mimic what is actually happening when the SARS-CoV-2 virus infects people. It was that.

“Science is the answer. When you use science to ask what’s wrong with lung cells when infected with a coronavirus, the cells tell us,” says Cotton. “Objective scientific data gives us hints on what to do and has lessons to teach us. It can reveal the path from this pandemic.”

He is particularly excited about the outreach the team has received from collaborators around the world. “People with supercomputer and machine learning expertise are excited to use these tools and our publication datasets to identify the most promising drug discovery targets. [for treating COVID-19]”He says.

Cotton says the theme that emerged between COVID-19 clinicians and scientists understands that timing is important. “When patients are on the ICU ventilator, we feel that there is a limit to what they can do with their bodies,” he says. “Timing is everything. It’s important to identify the early stages of intervention opportunities. You keep guessing and hope we’re lucky-or you [do the research] To actually understand the infection from the beginning and remove guesswork from drug development. “

Reference: “Practical cytopathogenicity of human alveolar type 2 cells against SARS-CoV-2” by Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, Kristine M. Abo, Jessie Huang, Benjamin C. Blum, Rhiannon B Sexual Host Response “. Werder, Ellen L. Suder, Indranil Paul, Sadhna Phanse, Ahmed Youssef, Konstantinos D. Alysandratos, Dzmitry Padhorny, Sandeep Ojha, Alexandra Mora-Martin, Dmitry Kretov, Peter EA Ash JJ Villacorta-Martin, Dante Bolzan, Carlos Perea-Resa, Esther Bullitt, Anne Hinds, Andrew Tilston-Lunel, Xaralabos Varelas, Shaghayegh Farhangmehr Ulrich Braunschweig, Julian H. Kwan, Mark McComb, Avik Basu, Mohsan Saeed , Matthew D. Layne, John H. Connor, Robert Davey, Ji-Xin Cheng, Benjamin L. Wolozin, Benjamin J. Blencowe, Stefan Wuchty, Shawn M. Lyons, Dima Kozakov, Daniel Cifuentes, Michael Blower, Darrell N. Kotton, Andrew A. Wilson, Elke Mühlberger, Andrew Emili, November 18, 2020, Molecular cell..
DOI: 10.1016 / j.molcel.2020.11.028

This study was funded by the National Institutes of Health, the Australian National Council for Health Medicine, the Pulmonary Fibrosis Foundation, the Massachusetts Consortium on Pathogen Preparation, the C3.ai Digital Conversion Institute, the Canadian Institute of Health, and Fast Grants. ..