BU researchers discover how COVID-19 may trigger fatal levels of lung inflammation

September 21, 2020

(Boston)-- Responding to the COVID-19 pandemic caused by the novel coronavirus, SARS-CoV-2, requires models that can duplicate disease development in humans, identify potential targets and enable drug testing. Specifically, access to primary human lung in vitro model systems is a priority since a variety of respiratory epithelial cells are the proposed targets of viral entry.

Now, a team of infectious disease, pulmonary and regenerative medicine researchers at Boston University, studying human stem cell-derived lung cells called type 2 pneumocytes, infected with SARS-CoV-2, have shown that the virus initially suppresses the lung cells' ability to call in the help of the immune system with interferons to fight off the viral invaders and instead activates an inflammatory pathway called NFkB. "The infected lung cells pour out inflammatory proteins. In the body of an infected person, those proteins drive up levels of inflammation in the lungs," explains corresponding author Darrell Kotton, MD, the David C. Seldin Professor of Medicine at BUSM and Director of the BU/BMC Center for Regenerative Medicine (CReM).

According to the researchers, the inflammatory signals initiated by the infected pneumocytes attract an army of immune cells into lung tissue laden with infected and already dead and dying cells. "Our data confirms that SARS-CoV-2 blocks cells from activating one of the anti-viral branches of the immune system early on after infection has set in. The signal the cells would typically send out, a tiny protein called interferon that they exude under threat of disease, are instead delayed for several days, giving SARS-CoV-2 plenty of time to spread and kill cells, triggering a buildup of dead cell debris and other inflammation," added Kotton.

The data is based on experiments the research team performed in the laboratory of co-senior author Elke Mühlberger, PhD, associate professor of microbiology at BUSM and a researcher at BU's National Emerging Infectious Diseases Laboratories (NEIDL). Kotton and other members of the CReM have developed sophisticated models of human lung tissue--three-dimensional structures of lung cells, called "lung organoids," grown from human stem cells--which they've used at BU and with collaborators elsewhere to study a range of chronic and acute lung diseases.

The research team, led by co-first authors, Jessie Huang, PhD, Kristy Abo, BA, Rhiannon Werder, PhD and Adam Hume, PhD, adapted an experimental model previously used to study the effects of smoking cigarettes to study the coronavirus in lung tissue. Droplets of live coronavirus were then added on top of the lung cells, infecting them from the air the way the virus infects cells lining the inside of the lungs when air containing the virus is breathed into the body. "This adaptation of human stem cell-derived pneumocytes to air, known as an 'air-liquid interface' cell culture was a key advance that allowed us to simulate how SARS-CoV-2 enters cells deep in the lungs of the most severely affected patients," said co-senior author Andrew Wilson, MD, associate professor of medicine at BUSM. "Type 2 pneumocytes are also infected and injured in patients with COVID-19, making this a clinically meaningful system to understand how the disease injures patient lungs."

Wilson and Kotton, are also pulmonary and critical care physicians taking care of patients with COVID-19 pneumonia at Boston Medical Center, while also leading their laboratories to produce the human lung cells that were then transported into the NEIDL. There Hume, a senior research scientist in the Mühlberger's lab, worked in a BSL-4 suit to perform the infections of the cells that the three collaborating teams then analyzed together through weekly zoom calls.

"These cells are an amazing platform to study SARS-CoV-2 infection," adds Mühlberger. "They likely reflect what is going on in the lung cells of COVID-19 patients. If you look at the damage SARS-CoV-2 inflicts on these cells, you definitely don't want to get the disease."
These findings appear online in the journal Cell Stem Cell.

Funding for this study was provided by Evergrande MassCPR awards, the National Institutes of Health, a CJ Martin Early Career Fellowship from the Australian National Health and Medical Research Council, an I. M. Rosenzweig Junior Investigator Award from the Pulmonary Fibrosis Foundation, a Harry Shwachman Cystic Fibrosis Clinical Investigator Award, the Gilead Sciences Research Scholars Program, Gilda and Alfred Slifka and Gail and Adam Slifka funds, a Cystic Fibrosis Foundation grant, and a Fast Grants award.

Read the full story and watch a video animation on The Brink

Boston University School of Medicine

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.