Penn Researchers Identify Missing Link for Fighting Viral Pneumonia

Viral infections that occur in a patient’s lungs are a significant cause of hospitalization and death among children and the elderly. According to the Centers for Disease Control, respiratory syncytial virus (RSV) causes about 60,000 hospitalizations of children aged 0 to four, and nearly 200,000 hospitalizations and 14,000 deaths among adults 65 and older. However, there are virtually no vaccines or treatments for these infections. In a study published online ahead of print in PLoS Pathogens, researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Pennsylvania School of Veterinary Medicine found evidence that the cytokine, Interleukin 27 (IL-27), may be the key to fighting and treating these infections.

Working with a mouse-model of parainfluenza virus infection, Sendai virus, which causes similar symptoms and patterns of tissue damage to RSV, researchers found that mice fared much worse in fighting the infection when their cells lacked IL-27 signaling.

“IL-27 is a specific cytokine naturally produced by immune cells to regulate the response to infection, limiting symptoms such as severe airway inflammation,” said Gaia Muallem, MD, a Perelman School of Medicine Measey Fellow in the division of Renal, Electrolyte and Hypertension. “Our recognition of IL-27’s importance in mouse models could lead to improved diagnosis and prevention of lung disease following a viral infection in human patients.”

When the researchers blocked IL-27 signaling – by genetically engineering mice to lack working IL-27 receptors or IL-27 proteins – infected mice suffered much worse illness and higher mortality. Since virus levels stayed the same in all of the mice, more severe illness resulted from an excessive immune reaction in those mice without IL-27. Other researchers have shown that while the immune response Th1 is necessary to clear such viruses, another response, Th2, which is associated with severe airway inflammation and the development of post-infection asthma, could arise after viral infection. Originally, researchers thought Th2 response had evolved to promote tissue repair; however, in the context of lung virus infections, Th2 cells appear to contribute to the overactive immune responses that endanger patients.

In this study, immune cell infiltration of the lungs increased, and Th2 responses became more prominent. Previous studies have found evidence that IL-27 has a moderating effect on the Th2 response, and in general, keeps T-cells – the “battle tanks” of the immune system – from causing too much damage.

“The suggestion here is that IL-27 normally limits the severity of disease during these viral infections in part by influencing the quality of T-cell responses,” Muallem said. “Other studies have also linked variants of the IL-27 gene with chronic or severe lung disease, so in theory, we might be able to test for such variants to identify people who are more at risk of complications from these lung infections.”

Researchers note more animal studies are needed to determine whether the administration of IL-27 can successfully treat severe illness from these viral infections. In principle, IL-27 could be delivered via an intranasal spray, so the effects would be isolated to the airways, and not affect other parts of the body.

Additional authors on this study include senior authors Carolina B. López and Christopher Hunter from Penn Vet, along with Sagie Wagage, Yan Sun, Jonathan H. DeLong, Alex Valenzuela, David A. Christian, Gretchen Harms Pritchard, Qun Fang, Elizabeth L. Buza, and Deepika Jain, all of Penn; and M. Merle Elloso of Janssen Research & Development.

This study was supported by the American Asthma Foundation Senior Investigator Award, the Measey Senior Research Fellowship, the American Society of Nephrology Ben Lipps Research Fellowship, and grants from the Nation Institute of Health (R01 AI110201), (5T32DK007006-41), (R01 AI083284), (R21 AI109472).

Source: Perelman School of Medicine at the University of Pennsylvania