First defence: how airways remove infected cells

The epithelium, a layer of cells that forms a protective barrier between the body and the outside world, was the first organised tissue to evolve. Epithelial cells lining our airways are mainly seen as a structural barrier, but cell biologist Jody Rosenblatt, who runs a lab at the Crick and King's College London, believes their evolutionary history suggests they're playing a much more active role in infections.

"The airway lining is the body's first physical barrier against inhaled threats like viruses," says Jody. "It would make sense for it to take direct action."

To investigate this, Jody's team studied rhinoviruses, which are the leading cause of the common cold. They usually cause mild illness, but they can cause more serious respiratory disease in young children, older people, people with weakened immune systems and those with chronic lung conditions such as asthma or COPD.

Their new study, published today in Science Advances, shows that airway cells respond to rhinovirus infection by physically pushing infected cells out of the tissue, in a process the researchers have named 'virus-induced cell extrusion' or 'VICE'.

As first author and Postdoctoral Research Fellow Faith Fore explains, "We studied rhinovirus infection in human epithelial cells grown in the lab, and we observed that when the cells were able to work together as a healthy layer, they could remove infected cells and limit infection within the tissue.

"But when we experimentally disrupted the barrier by breaking down junctions between epithelial cells, more virus particles built up in the epithelial layer. We also observed virus-induced cell extrusion in mouse lung tissue, supporting the relevance of the mechanism in a more complex tissue environment."

The researchers also observed that VICE happens in two distinct waves. The first begins rapidly, before the virus has fully entered the cell, involving the cell's ability to sense mechanical changes, while a second wave occurs later, triggered by the virus replicating inside the cell, leading to cell death. "These two waves allow the epithelial cells to kick into action straight away, without the need for signals from immune cells that have recognised the virus," says Jody.

A 'double-edged defence'

This early defence mechanism helps remove most infected cells from the airway lining within 24 hours, maintaining the integrity of the barrier. But, there's a downside. "The expelled cells remain alive and infectious, potentially allowing the virus to reach new cells," explains Faith. The team confirmed this by adding extruded airway cells to healthy cells in a dish, which subsequently were infected with the virus after just six hours.

Faith continues, "The airway gets rid of the infected cell, but it doesn't destroy the virus. Because the expelled cells can still infect new cells, it creates a double-edged defence. Extrusion helps the tissue clear the immediate infection, but the expelled cells remain a potential source of viral spread."

An overlooked mechanism

Jody believes that this mechanism should be taken into account when assessing responses to infections. It may have been overlooked because some commonly used laboratory models do not recreate the cell-to-cell junctions that the team has now shown are required for VICE to occur.

"Our study suggests that cells lining our tissues possess evolutionarily ancient mechanisms for protecting themselves," she says. "Understanding these fundamental tissue defence mechanisms could change how we think about the earliest stages of viral infection."

Faith agrees, "We typically think of the cells lining our airways as a simple physical barrier, leaving the heavy lifting of clearing infections to the immune system. What we found is that the epithelium itself actively fights back by physically throwing out infected cells."

The researchers are now planning to investigate how widespread this defence mechanism is across respiratory viruses, what determines whether extrusion protects the airway or promotes viral spread, and how viruses might evade or exploit the response.

Adapted from an article from King's College London.