A Greek-led international research team has identified a key immune system receptor that could pave the way for new treatments for idiopathic pulmonary fibrosis (IPF), a rare and life-threatening lung disease with limited treatment options.
The study, led by Greek pulmonologist Dr Stavros Garantziotis, was published in Science Translational Medicine and reveals how the lung microbiome may contribute to the development of the disease while identifying the immune receptor TLR5 as a promising therapeutic target.
Idiopathic pulmonary fibrosis causes progressive scarring of the lungs, leading to irreversible loss of lung function and, ultimately, respiratory failure. Current medications can only slow the disease’s progression.
Dr Garantziotis, a researcher at the US National Institute of Environmental Health Sciences (NIEHS), said he turned his attention to the disease because of its poor prognosis.
“When, as a doctor, you realise there is very little you can do for your patients, you want to understand the mechanisms behind the disease,” he said.
“Medicine is no longer purely empirical. Every patient is different. If we understand what causes the disease in each individual, we can develop treatments that target the root of the problem with much greater precision.”
Although the exact cause of IPF remains unknown, smoking and environmental pollution are recognised risk factors.
The researchers identified another critical factor: the lung microbiome.
For many years, scientists believed healthy lungs were sterile. Modern research has overturned that assumption, showing the lungs constantly interact with the outside environment and host diverse microbial communities.
The team found that environmental damage, including cigarette smoke, may disrupt the balance of bacteria in the lungs, triggering chronic inflammation that eventually leads to the scarring characteristic of pulmonary fibrosis.
TLR5 plays a protective role
The research focused on TLR5, an immune receptor responsible for recognising certain bacteria and activating protective immune responses.
Researchers analysed genetic data from more than 1,100 patients with idiopathic pulmonary fibrosis and approximately 2,500 healthy individuals.
They found a clear association between IPF and reduced TLR5 function.
The team then confirmed the finding in laboratory mice. Animals lacking a functional TLR5 receptor proved significantly more susceptible to developing pulmonary fibrosis.
Further experiments demonstrated that activating TLR5 using a specific bacterial protein stimulated the receptor’s protective function, effectively shielding animal models from developing lung fibrosis.
Potential benefits extend to COPD
A second study by the same research group, currently awaiting publication, suggests TLR5 may also protect against chronic obstructive pulmonary disease (COPD).
The researchers examined COPD patients, human cells and animal models, finding that higher TLR5 activity in the lungs corresponded with lower levels of inflammatory markers in patients’ blood.
They also discovered that cigarette smoke suppresses TLR5 expression in airway cells.
Dr Garantziotis said the findings suggest smoking may damage the lungs partly by reducing TLR5 activity, leading to poorer lung health and increased bacterial growth.
“The activation of TLR5 may improve lung function,” he said, adding that restoring the receptor’s activity could become a new therapeutic strategy for chronic lung diseases.
Next steps toward treatment
The research team will now investigate which antibiotics may best restore healthy lung bacteria and whether medicines that directly activate TLR5 can prevent or treat pulmonary fibrosis.
Dr Garantziotis was born and raised in Athens before studying medicine at Germany’s Albert Ludwig University of Freiburg. He completed specialist training in Internal Medicine at Albert Einstein College of Medicine in New York and Pulmonary Medicine at Duke University in North Carolina.
He has served for approximately 15 years as Director of the Clinical Research Unit at the US National Institute of Environmental Health Sciences.
The full study, “TLR5 protects against pulmonary fibrosis by preserving the lung microbiome,” appears in Science Translational Medicine.