Team explores diabetes drug's ability to treat RSV infection

July 13, 2018 by Liz Entman, Vanderbilt University
Team explores diabetes drug’s ability to treat RSV infection
The team studying a diabetes drug’s ability to treat RSV includes, from left, Kevin Niswender, MD, PhD, R. Stokes Peebles, MD, Tina Hartert, MD, MPH, Lisa Bastarache, MS, and Melissa Bloodworth, PhD. Credit: Joe Howell

A drug used to treat diabetes may point to new therapies for respiratory syncytial virus (RSV) bronchiolitis—inflammation and obstruction of the lungs' small airways. A multi-disciplinary team of Vanderbilt investigators has demonstrated that liraglutide reduces the inflammatory response to RSV infection in a mouse model of the disease.

The findings were reported in the Journal of Allergy and Clinical Immunology.

Liraglutide is one of six "GLP-1R agonists" approved to treat type 2 diabetes. These drugs enhance insulin secretion from the pancreas by activating the glucagon-like peptide 1 receptor (GLP-1R).

"The connection between GLP-1R signaling and lung inflammation was a surprise," said R. Stokes Peebles, MD, Elizabeth and John Murray Professor of Medicine. His team was exploring a suggestion from a friend and colleague who studies diabetes and obesity, Kevin Niswender, MD, Ph.D., associate professor of Medicine.

The two have co-coached their daughters' basketball teams for the past several years.

"One day after practice, Kevin said, 'you need to look at these drugs in your models,'" Peebles said.

Niswender explained that GLP-1R agonists have anti-inflammatory properties, but the drugs hadn't been examined in the type of allergy and virally mediated airway inflammation that Peebles and his team study.

"We'll almost always try out a new idea because you never know what might hit," Peebles said.

Melissa Bloodworth, Ph.D., a student in the MD/Ph.D. program, infected mice with a strain of RSV that had been isolated from an infant who was hospitalized with severe lower and bronchiolitis. The RSV strain induced high levels of inflammatory factors and airway mucus in mice, conditions that mimicked severe infection in patients.

Treatment of the mice with liraglutide, before or after RSV infection, decreased production of inflammatory factors in the lungs and reduced inflammation, airway responsiveness and airway mucus.

"This drug worked really well to decrease the pathology that occurs in the lungs, suggesting its potential for treating severe RSV infection," Peebles said.

RSV bronchiolitis is the No. 1 cause of hospitalization for infants in the United States, with up to 125,000 children hospitalized each year, according to the National Institute of Allergy and Infectious Diseases. Adults older than 65 are also vulnerable to lung disease from severe RSV infection.

Infants and children at high risk for RSV bronchiolitis can receive the drug palivizumab to prevent RSV infection, but there are no treatment options after RSV infection occurs.

"A vast number of children who don't have any risk factors get RSV bronchiolitis and are hospitalized, and they are the patients that a drug like liraglutide potentially could help," Peebles said.

Niswender is working with medicinal chemists at Vanderbilt to develop more effective GLP-1R agonists that can be targeted specifically to the lungs via inhalation.

Bloodworth also measured the antiviral immune response in mice infected with RSV and treated with liraglutide.

She found no difference in mediators of the antiviral immune response, including interferon-gamma and certain white blood cells (Th1 T helper cells and natural killer cells).

"This was important because we wouldn't want to pursue a treatment for RSV that has a negative effect on the antiviral immune response," Bloodworth said.

Bloodworth also found that liraglutide treatment of a first RSV infection did not block a protective immune response to a second RSV infection in mice.

To search for a connection between GLP-1R signaling and human RSV disease, the researchers conducted a Phenome-Wide Association Study (PheWAS) with Lisa Bastarache, MS, lead data scientist in the Center for Precision Medicine. PheWAS searches for associations between known genetic variants and phenotypes (such as diagnoses) in the medical record.

Using existing databases, the investigators identified a genetic variant associated with a lower response to GLP-1. Then they conducted a PheWAS for that variant in Vanderbilt's BioVU biobank. They found that the gene variant was associated with acute bronchiolitis.

"The fact that we found an association between GLP-1R signaling and human bronchiolitis corroborates our mouse studies and is very exciting," Bloodworth said.

The studies have opened an entirely new area of research, Peebles said.

"The GLP-1 receptor is highly expressed in the lung, but no one knows what it's doing," he said. "We're working on understanding the role of endogenous GLP-1 receptor signaling in the lungs—what happens if the receptor is missing and what happens in the setting of allergic and viral inflammation."

Peebles and his colleagues are also exploring the use of GLP-1R agonists in people who have obesity and asthma.

"There's an epidemic of asthma in people who are obese, and we're interested in these drugs as a potential therapy for both obesity and asthma related to obesity," he said.

The RSV strain used in the was isolated from an infant enrolled in a study of RSV and asthma directed by Tina Hartert, MD, MPH, Lulu H. Owen Professor of Medicine, and supported by an Asthma and Allergic Diseases Cooperative Research Center grant. Martin Moore, Ph.D., at Emory University, isolated and grew the viruses.

Explore further: Two novel immune-response clusters identified to RSV

More information: Melissa H. Bloodworth et al. Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus–induced type 2 responses and immunopathology, Journal of Allergy and Clinical Immunology (2018). DOI: 10.1016/j.jaci.2018.01.053

Related Stories

Two novel immune-response clusters identified to RSV

May 21, 2018
(HealthDay)—Two novel immune-response clusters have been identified to respiratory syncytial virus (RSV), and they are associated with first- and second-year recurrent wheeze, according to a study published online May 7 ...

Treatment strategy may reduce infants' wheezing caused by virus

November 19, 2014
(Medical Xpress)—The antibiotic azithromycin may reduce the risk of recurrent wheezing in infants hospitalized with a common respiratory infection, according to a small pilot study at Washington University School of Medicine ...

DNA-modulating drug attenuates lung inflammation in mice

July 21, 2016
Patients with cystic fibrosis (CF) suffer from chronic respiratory infections, primarily caused by Pseudomonas aeruginosa, which lead to airway inflammation and damage. Several recent studies have suggested that a specific ...

Scientists discover peptide that could reduce the incidence of RSV-related asthma

February 1, 2017
A research report published in the Journal of Leukocyte Biology shows that it may one-day be possible to reduce the incidence of asthma related to infection with respiratory syncytial virus (RSV). Specifically, the researchers ...

New molecular target could help ease asthma

March 7, 2018
Researchers at UC Davis Health and Albany Medical College have shown that the protein vascular endothelial growth factor A—or VEGFA—plays a major role in the inflammation and airway obstruction associated with asthma.

Early childhood bronchiolitis increases asthma risk in adulthood

November 23, 2015
Persons who have had bronchiolitis in early childhood have an increased risk of asthma at the age of 28-31 and a weaker health-related quality of life than their peers. In lung function tests, they also demonstrate changes ...

Recommended for you

Paracetamol use in infancy is linked to increased risk of asthma in some teenagers

September 17, 2018
Children who take paracetamol during their first two years of life may be at a higher risk of developing asthma by the age of 18, especially if they have a particular genetic makeup, according to new research presented at ...

Cord blood clue to respiratory diseases

September 15, 2018
New research has found children born in the last three months of the year in Melbourne may have a greater risk of developing respiratory diseases such as asthma.

FRESH program combines basic science with social benefits for women at risk of HIV

September 14, 2018
A program established by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard is addressing the persistently elevated risk of HIV infection among young women in South Africa from ...

Dietary fiber reduces brain inflammation during aging

September 14, 2018
As mammals age, immune cells in the brain known as microglia become chronically inflamed. In this state, they produce chemicals known to impair cognitive and motor function. That's one explanation for why memory fades and ...

Research reveals link between immunity, diabetes

September 14, 2018
When it comes to diet-induced obesity, your immune system is not always your friend.

Immune response mechanism described for fate determination of T cells

September 13, 2018
After a pathogen infects the body, the immune system responds with a remarkable—and remarkably complicated—cascade of events.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym625810
not rated yet Jul 13, 2018
I was diagnosed with type 2 Diabetes and put on Metformin on June 26th, 2017. I started the some diet and followed it 100% for a few weeks and could not get my blood sugar to go below 140. Finally i began to panic and called my doctor, he told me to get used to it. He said I would be on metformin my whole life and eventually insulin. At that point i knew something wasn't right and began to do a lot of research. Then I found Lisa's diabetes story (google " How I freed myself from diabetes " ) I read that article from end to end because everything the writer was saying made absolute sense. I started the diet that day and the next week my blood sugar was down to 100 and now i have a fasting blood sugar between Mid 70's and the 80's. My doctor took me off the metformin after just three week of being on this lifestyle change. I have lost over 16 pounds and 3+ inches around my waist in a month.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.