The National Heart, Lung, and Blood Institute (NHLBI) of the NIH recently awarded CBMG Assistant Professor Dr. Margaret Scull a 5-year, $2.7 million grant to support her team’s efforts in researching the role of airway mucins during influenza virus infection.
As a respiratory virus, influenza targets specific cells in the human airway–termed epithelial cells–for infection. Standing between the virus and these cells, however, is the mucosal barrier that acts to trap and remove viruses, bacteria, and other particulate matter we inhale. This barrier has two parts – a secreted mucus gel and underlying layer mucins, a family of extremely large molecules that are coated in glycans, or sugars, are a major component of both parts. However, studying mucins in their native setting is not simple. “Most cell culture systems fail to replicate this barrier, so our basic understanding of how specific mucins contribute to airway biology and provide defense against invading pathogens is incomplete,” Scull says.
Scull’s team has been using an in vitro model of human airway epithelium that ‘looks’ and ‘acts’ very much like the epithelium in our lungs. Scull is particularly interested in MUC1, a unique mucin protein that is tethered to the surface of epithelial cells and can act as both a physical barrier and signaling molecule. “We’re learning that some of these mucins, MUC1 included, are more dynamic than we originally envisioned,” Scull says. “They are more than just a simple, static shield.”
With this new award, Scull will define how MUC1 expression, specifically on epithelial cells and cells that contribute to the immune response, such as macrophages, impacts the course of influenza virus infection. Her laboratory will detail the molecular interactions of MUC1 with both influenza virus and cellular factors, aiming to shed new light on the influence of this particular mucin in virus infection and host defense.
As influenza virus tends to bind to the same kind of sugar molecules that are attached to the surface MUC1, it is likely that the virus interacts directly with this molecule during infection. Yet the consequence of this interaction for both virus and mucin is not clear, and hints that MUC1’s influence on infection may be specific to the strain of virus involved.
To tackle these questions, Scull proposes to utilize new mouse models and modified human airway epithelial cultures. Her lab recently established methods to apply CRISPR technology in these cultures, making the cell-virus interaction more genetically tractable, and expanding their ability to pinpoint the role of specific cell factors during infection. “It’s been exciting to see developments in this field over the past decade that have made the human airway epithelial culture system less expensive and more flexible. The technology enables us to grow, manipulate, and assay these cells in new ways, so that we can ask questions in this system that were not possible before,” Scull notes.
This work stands to support further development of mucin mimics, or small molecules that can impact mucin signaling activity and help clear influenza virus from the lung.