Scientists Identify New Strategy to Fight Deadly Infection in Cystic Fibrosis
The research group showed that rapamycin, an existing drug known to stimulate autophagy, helped control B. cenocepacia infection in mice that serve as a model for cystic fibrosis.
“Rapamycin worked well as a proof of concept, but it has so many side effects that it’s hard to imagine giving it to small children with CF for an extended period of time. That’s why we looked for another method,” said Amer, also an investigator in Ohio State’s Center for Microbial Interface Biology (CMIB).
For this study, the researchers conducted experiments in macrophage cells derived from mice carrying the CF mutation and compared them to macrophages from normal, healthy mice.
The researchers observed in macrophages with the mutation that when p62 is elevated, other cell components clump together, causing disruption to the autophagy process.
How common is CF?
Cystic fibrosis is the most common genetically-inherited life-shortening chronic illness affecting young Australians today. A baby is born with cystic fibrosis every four days.
In Australia, one in 25 people are carriers of the CF gene. Carriers of the CF gene do not have any symptoms of the condition. If two people carry the gene and have a child, each pregnancy will have:
A one in four chance that the child will have CF
A two in four chance that the child will not have CF but will carry the gene
A one in four chance that the child will not have CF and will not be a carrier.
One in every 2,500 births produces a child with CF. Approximately 3,000 people in Australia have CF.
CF is usually diagnosed at birth
In most Australian States all babies are screened at birth for CF through the newborn screening test. This involves collection of a blood sample. If the results of the screening test reveal very high levels of a substance called immunoreactive trypsin (IRT), CF is suspected and the DNA in the blood is then analysed for the most common mutation-causing CF.
A sweat test may be done to measure the amount of salt (sodium chloride) in the sweat and confirm the diagnosis.
Some babies may also be diagnosed shortly after birth as a result of an intestinal blockage called meconium ileus. Most babies who have CF are now diagnosed within the first two months of life.
“p62 is a sticky protein, so high levels of it lead to the formation of aggregates. Once we get rid of that sticky protein – the glue – these protein aggregates will be able to go where they are supposed to go and allow the autophagy process to work properly,” Amer said.
Abdulrahman observed that in cells with the CF mutation, a key molecule gets caught up in those clumps. This molecule, beclin1, has a critical autophagy job, essentially escorting foreign particles to the cell parts that digest them and clear them away.
“Our hypothesis was that if we downregulate p62, this will release beclin1 from the aggregates. Once it’s available, we will have active autophagic machinery that is able to control the infection,” said Abdulrahman, first author on the paper.
In contrast, lowering p62 in macrophages from normal mice allowed the B. cenocepacia bacteria to grow. This confirmed that p62 actually controls the infection in cells from healthy animals but has the opposite effect when the CF mutation is present, she said.
This work is supported by the National Institutes of Health, Cystic Fibrosis Canada and an Egyptian Bureau of Education fellowship.
Additional co-authors are Arwa Abu Khweek, Kyle Caution, Mia Tazi, Hoda Hassan, Yucheng Zhang; Sankalp Malhotra and Patrick Rowland of the Department of Microbial Infection and Immunity, Department of Internal Medicine and CMIB; and Famke Aeffner and Ian Davis of the Medical Scientist Training Program and Department of Veterinary Biosciences, all at Ohio State; and Miguel Valvano of the University of Western Ontario and Queen’s University.
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Contact: Amal Amer, (614) 247-1566; .(JavaScript must be enabled to view this email address) or Basant Abdulrahman, .(JavaScript must be enabled to view this email address) (Abdulrahman is now working in Egypt).
Written by Emily Caldwell, (614) 292-8310; .(JavaScript must be enabled to view this email address)
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The Ohio State University