Researchers at the University of Queensland have identified an opportunity to reduce infections in people living with cystic fibrosis (CF). Professor Matt Sweet, Dr Kaustav Das Gupta and Dr James Curson from UQ's Institute for Molecular Bioscience have discovered a flaw in the bacteria-killing function of immune cells in people with cystic fibrosis and a potential way around it.
The study was published in the journal Proceedings of the National Academy of Sciences.
Cystic fibrosis: the importance of zinc
Cystic fibrosis is a chronic disease in which defects in the cystic fibrosis transmembrane conductance regulator (CFTR) channel cause a buildup of mucus in the lungs, airways, and digestive system, leading to recurrent infections.
Professor Sweet said the team found that in people with cystic fibrosis, immune cells called macrophages are defective in the zinc pathway that the body uses to kill bacteria.
“One way macrophages destroy bacteria is by poisoning them with toxic levels of metals such as zinc,” Professor Sweet said.
“We found that the CFTR ion channel is crucial to the zinc pathway, and because it doesn't work properly in people with cystic fibrosis, it could partly explain why they are more susceptible to bacterial infections.”
Importantly, the researchers also identified a zinc transport protein that can restore macrophages' ability to kill bacteria when the CFTR protein fails.
“Our aim now is to deliver this zinc transport protein to macrophages in people with cystic fibrosis with the expectation that it will reactivate their immune response and reduce infections,” Professor Sweet said.
Around 3,600 Australians are living with cystic fibrosis, which can reduce life expectancy to an average of 47 years.
Professor Peter Sly of UQ's Child Health Research Centre, a pediatric pulmonologist and key collaborator on the project, said finding out more about how cystic fibrosis affects the immune system is crucial to patient care.
“People with cystic fibrosis have a hyperinflammatory state in the airways and are very susceptible to bacterial infections, but frequent treatment with antibiotics can often lead to antibiotic-resistant infections,” Professor Sly said.
“Current treatments can restore many aspects of CFTR function but do not resolve or prevent lung infections, so restoring immune functions is necessary.”
Stem cells cause disease in the lungs of cystic fibrosis patients
Two nationally recognized experts in cloning and stem cell science at the University of Houston, Wa Xian and Frank McKeon, report that five lung stem cell variants dominate the lungs of patients with advanced cystic fibrosis (CF) and that these variants determine key aspects of cystic fibrosis pathology including inflammation, fibrosis and mucin secretion.
Cystic fibrosis is an inherited, progressive disease that causes long-lasting lung infections and limits the ability to breathe. It is caused by a defect in a gene called cystic fibrosis transmembrane conductance regulator (CFTR) and affects nearly 40,000 people in the United States. Defects in the CFTR gene lead to the production of abnormally sticky, thick mucus that clogs organs, particularly the lungs, causing a chronic lung disease characterized by infection and inflammation.
Recently introduced drugs, known as CFTR modulators, work to restore the function of the mutant CFTR gene and produce dramatic improvements in the lung function of cystic fibrosis patients. However, in patients with established lung disease, lung inflammation persists despite treatment with CFTR modulators. This persistence is concerning as inflammation is believed to be a key factor in the progression of CF lung disease.
This gap in the effectiveness of the CFTR modulator makes the work of the Xian-McKeon laboratory particularly relevant.
“Using single-cell cloning technology that detailed stem cell heterogeneity in the lungs of patients with COPD and idiopathic pulmonary fibrosis (IPF), we identified five stem cell variants common in the lungs of patients with advanced cystic fibrosis, of including three that show hyperinflammatory gene expression profiles and drive neutrophilic inflammation following xenotransplantation in immunodeficient mice,” said Xian, research professor in biology and biochemistry.
“We found that CFTR-modulating drugs do not suppress the proinflammatory activity or gene expression of the three CF variants that drive inflammation,” reports McKeon, professor of biology and biochemistry and director of the Stem Cell Center, in the American Journal of Respiratory and Critical Care Medicine.
“These findings raise the possibility that these inflammatory stem cell variants are the source of persistent inflammation in patients treated with CFTR modulators.”
If true, their findings suggest that inflammatory stem cell variants are key targets for drug discovery to augment major therapeutic advances brought about by CFTR modulators. Identifying such lead drugs is an important effort in the Xian-McKeon laboratory, in collaboration with the Center for Drug Discovery, the UH Sequencing Center and colleagues in the Department of Chemistry and the Center for Biotechnology at Texas A&M in the Texas Medical Center.
The determinant of cystic fibrosis lung inflammation provides the target of treatment
Yale researchers have identified a possible trigger for the persistent inflammation that causes irreversible lung damage in patients with cystic fibrosis, a genetic disease that impairs breathing and digestion.
In a new study, they discover how a type of white blood cell called monocytes initiates a molecular chain of events that leads to prolonged inflammation in the lungs and damage to lung tissue. They also found that a drug that targets monocytes was able to slow the progression of tissue damage in a mouse model of cystic f
ibrosis, suggesting it could be an effective treatment for cystic fibrosis in the future.
Cystic fibrosis is a genetic disease that affects several organs in the body. In the lungs, the disease causes a buildup of mucus that traps bacteria and makes patients more susceptible to infections. Over time, as symptoms worsen, infections often become chronic for the rest of patients' lives.
Chronic inflammation is another complication of cystic fibrosis. Studies have shown that early in life, before infections become a problem, inflammation is already occurring.
“Children with cystic fibrosis may seem completely fine with normal respiratory function, but the reality is that the disease is already having an effect,” said Emanuela Bruscia, associate professor of pediatrics at Yale School of Medicine and senior author of the study. “Mucus is already building up and there are areas in the lung that are inflamed. And inflammation, if left uncontrolled, is harmful to any type of tissue.”
Over the past decade, new treatments for cystic fibrosis have helped extend life expectancy beyond 50 years. Such treatments, called CFTR modulators, target the malfunctioning protein – CFTR, or cystic fibrosis transmembrane conductance regulator – that causes cystic fibrosis symptoms. But while CFTR modulators help clear mucus in the lungs and maintain lung function, they don't completely address inflammation.
In the new study, researchers analyzed lung tissue taken from patients with advanced cystic fibrosis to better understand what drives inflammation in the lungs. They found that there were many monocytes in the damaged tissue areas, five to ten times more than those found in healthy lungs. So, to evaluate the role of monocytes in cystic fibrosis, they turned to a mouse model of chronic lung inflammation that shows similar levels of lung damage and functional decline to what is seen in cystic fibrosis patients.
“The question was how those cells participate in the disease,” Bruscia said.
They found that monocytes, when drawn into the lungs by the bloodstream, release chemical attractants that attract another type of immune cell called neutrophils into the lungs. And neutrophils cause tissue damage.
This can occur even in healthy lungs, including in response to an infection. But once the neutrophils and monocytes' work is done, those cells should go away. In cystic fibrosis, researchers have found that this is not the case.
“Pro-inflammatory monocytes are part of the normal immune response, but once they arrive and do their job, they should be instructed to go away and shut up,” Bruscia said. “But in cystic fibrosis they come in, they're super inflammatory, and then they find themselves in an environment where they can't leave and shut up, so they continue to produce these pro-inflammatory mediators.”
Because monocytes and neutrophils play a key role in the immune response, eliminating them entirely would not be beneficial, especially for cystic fibrosis patients battling chronic lung infections. Instead, Bruscia and his colleagues explored how to reduce the level of monocytes recruited to the lungs and bring their numbers to levels found in healthy lungs.
In their mouse model, they tested a small molecule called a CCR2 inhibitor. Monocytes found in excess in cystic fibrosis lungs have a protein on their surface called CC chemokine receptor type 2, or CCR2. The protein acts as a signal detector. And when an immune signal called a chemokine binds to CCR2, it causes the monocyte to move where it's needed. By inhibiting CCR2 with the drug, the researchers were able to reduce the number of monocytes recruited to the lungs of mice and slow the progression of tissue damage.
“Importantly, the CCR2 inhibitor did not block all monocytes. It just brought the numbers closer to healthy levels,” Bruscia said.
CCR2 inhibitors are currently undergoing clinical trials for other diseases, such as cancer. The results of this study suggest that they may also be effective in treating the chronic inflammation found in cystic fibrosis.
Bruscia and his colleagues are continuing to evaluate the effectiveness of CCR2 inhibitors in cystic fibrosis models, studying how they work in the context of lung infection and comparing different types to see which are most effective.
They will also continue to study what happens immunologically in the lungs of cystic fibrosis patients.
“There's so much going on in the lungs that we don't understand yet,” Bruscia said. “This is just the tip of the iceberg.”
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