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Scientists at Duke University have identified a type of lung cell that can repair its damaged DNA and survive an attack of the influenza A virus while other types of cells around it die. in mbad.
The discovery reveals more about the battle between cells and viruses at the lowest level, and can also provide important clues for respiratory conditions such as chronic obstructive pulmonary disease and asthma.
The resilient cell is called a club cell and is found in the narrowest airways just above the alveoli of the lungs where the gases are exchanged into the bloodstream, said Nicholas Heaton, badistant professor of molecular genetics and of Microbiology at the Duke School of Medicine. The normal function of the cell is to produce surfactants and to secrete various other proteins that cover the lining of the lungs. Their functions during a viral infection, however, have not been fully understood.
Heaton and his team discovered in 2014 that club cells could survive an influenza infection that would kill most cells. In a 2016 study, they saw club cells increase their protein production machinery during a viral attack and tell the immune system to produce high levels of pro-inflammatory molecules called cytokines.
The net result of club cell survival would be that the lungs remain somewhat hostile to new viruses even after the disappearance of the infection, Heaton said.
As evidence, he cites an intriguing index of the 2009 influenza pandemic: that year's influenza virus was actively replicating during the summer months, not its fall months and usual winter. That year, another seasonal virus based on RNA, respiratory syncytial virus (RSV), was unable to infect people at the same time as it would normally, as if the population was better able to resist.
"This suggests that the flu is making changes that will help you better withstand another respiratory infection," Heaton said. And the club's cells were probably players in this area.
"We knew from previous work that club cells could survive, but we did not know how," Heaton said.
In the latest work, published July 29 in Nature Microbiology, Heaton's lab, along with Sara Cherry, a colleague from the University of Pennsylvania, badyzed all the viral response pathways of the club cell during of the infection. They discovered that the club's cells were accelerating the repair of the disparity of DNA in response to the infection.
The weapon of choice for an invasive virus is the reactive oxygen it uses to damage all open and active sections of DNA within the host cell. Normally, this damage builds up to the point where the cell can no longer express the genes it needs to fight the virus, after which it dies.
But the club's cell is redoubling its efforts to repair the damage to the DNA and resolves the infection.
To confirm that this was the case, the researchers created an artificial virus that contained the RNA needed to truly mask all the DNA repair material in human club cells in culture, after which the cells club would die of the flu, just like other respiratory cells.
After repairing their damaged DNA and surviving the influenza infection, club cells continue their work of producing surfactants and chemicals that promote inflammation.
"If another virus presents itself, the environment in which it normally comes in is pretty antiviral," said Heaton, which could explain the mystery of the missing respiratory syncytial virus in 2009.
But survival of club cells is a double-edged sword, Heaton said. A pro-inflammatory environment helps control virus levels, but it's actually the overactivity of inflammation that can kill flu patients, often after they've cleared the flu virus. Club cells that survive and stay active may actually contribute to it.
"We now have a population of cells that, we know, are going to be hyperinflammatory at the back of an infection," Heaton said. "When we run out of club cells, there is less inflammation," which could be an important element in combating chronic obstructive pulmonary disease or asthma, Heaton said.
This research was funded by the National Institutes of Health, the Burroughs Wellcome Fund and Duke University. Duke has filed a provisional patent application to target DNA mismatch repair as a way of growing influenza vaccine strains in the laboratory.
References:
"DNA mismatch repair is required for innate host response and controls cell fate after infection with influenza virus", Benjamin Chambers, Heaton Brook, Keiko Rausch, Rebekah Dumm Jennifer Hamilton, Sara Cherry and Nicholas Heaton. Nature Microbiology, July 29, 2019. DOI: 10.1038 / s41564-019-0509-3
"Club Cells Surviving Influenza A, a Virus Infection Inducing Temporary Non-specific Antiviral Immunity", Jennifer Hamilton, David Sachs, Jean Lim, Ryan Langlois, Peter Palese and Nicholas Heaton. Proceedings of the National Academy of Sciences, March 21, 2016. DOI: 10.1073 / pnas.1522376113
"Long-term survival of influenza virus-infected club cells results in immunopathology", Nicholas S. Heaton, Ryan A. Langlois, David Sachs, John K. Lim, Peter Palese, and Benjamin R. tenOever. Journal of Experimental Medicine, August 18, 2014. DOI: 10.1084 / jem.20140488
Source: Duke University
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