Bacterial protein fragment corisin identified as a causal driver of pulmonary fibrosis and a promising therapeutic target
核心洞察
Researchers at the University of Illinois Urbana-Champaign (搜索) and Mie University found that the bacterial peptide corisin (搜索) directly drives pulmonary fibrosis (搜索) by disrupting the cell's mitochondrial quality-control system.
Corisin (搜索)-producing bacteria were detected in lung fluid from pulmonary fibrosis (搜索) patients, and neutralizing corisin with an antibody eliminated the fluid's lethal effects on healthy cells.
Mice engineered to continuously produce corisin (搜索) in their lungs spontaneously developed pulmonary fibrosis (搜索), while treatment with a corisin-binding antibody reduced fibrosis, disease severity, and improved survival.
A bacterial protein fragment called corisin (搜索) drives pulmonary fibrosis (搜索) by infiltrating and disrupting the cell's quality-control system, according to a new study led by researchers at the University of Illinois Urbana-Champaign (搜索) and Mie University in Japan. The findings, published in the journal Nature Communications, move corisin from "simply an intriguing bacterial peptide associated with fibrosis to a mechanistically defined, biologically active and causally supported driver of disease — and importantly, a promising therapeutic target," said Illinois animal sciences professor Isaac Cann, who led the study with Mie University immunology professor Dr. Esteban Gabazza.
Tissue fibrosis is a process by which healthy tissue is progressively damaged or killed and replaced by scar tissue. It can occur in the lungs, kidneys, liver, heart, skin and other organs, and fibrosis contributes to nearly half of all deaths in developed countries, Gabazza said.
From association to causal driver
In 2020, Cann and Gabazza's team identified corisin (搜索), a peptide fragmented from a protein produced by bacteria that are a natural part of the human gut microbiome, as having the ability to kill lung cells and advance pulmonary fibrosis (搜索). However, key questions remained: how corisin reaches the lungs, and whether it directly drives fibrosis or merely exacerbates it.
Although earlier work found that corisin (搜索) can travel from the gut through the bloodstream, the researchers investigated whether corisin could also be produced locally in the lungs by bacteria residing in the respiratory tract. Analyzing fluid samples from the lungs of patients with pulmonary fibrosis (搜索) — collected at a hospital in Japan during routine clinical care, as well as during acute episodes of worsening disease — and comparing them to control samples from healthy volunteers, the team found corisin-related bacterial DNA in the fluid. This represented the first evidence that the peptide-producing bacteria were present in the lungs.
Demonstrating biological activity in patients
To confirm that the corisin (搜索) present in patients is biologically active, the researchers removed corisin from the patient fluid samples using an antibody they developed. The corisin-free fluid lost its lethal effects when applied to healthy cell cultures, demonstrating that corisin present in patients is capable of directly damaging lung cells. "Specifically neutralizing corisin with the antibody largely protected the cells from injury," Cann said.
The researchers then investigated the mechanism of corisin (搜索)'s damage. They found that once the peptide infiltrates the cells lining the lungs, it accumulates in the mitochondria, the organelle responsible for producing energy and for quality control of the proteins made by the cell's machinery. Corisin disrupts this quality-control system, triggering oxidative stress, premature cellular aging, cell death and scarring.
Local production drives fibrosis in vivo
To further establish that fibrotic effects can arise from corisin (搜索) produced locally in the lungs — rather than from peptides that traveled from the gut through the bloodstream — the researchers engineered mice to continuously produce corisin in their lungs. The mice spontaneously developed pulmonary fibrosis (搜索), with no outside bacterial source of the peptide.
"Our experiments also revealed that corisin (搜索) is remarkably potent. Corisin produced naturally exerts its harmful effects at extremely low levels. This tells us that even tiny amounts of native corisin are sufficient to trigger significant biological effects, making it directly relevant to human disease rather than simply an experimental observation," said Gabazza, who is also a U. of I. adjunct professor of animal sciences.
When treated with the researchers' corisin (搜索)-binding antibody, the mice showed significantly reduced pulmonary fibrosis (搜索), decreased disease severity and improved survival.
A new therapeutic strategy
"Together, these results provide compelling proof of concept that neutralizing corisin (搜索) could represent an entirely new therapeutic strategy for pulmonary fibrosis (搜索) and, potentially, fibrotic diseases affecting other organs," Cann said.
The researchers plan to continue refining treatment options related to their antibody, for which they have a patent pending, to block corisin (搜索) before it enters cells. They also plan to explore therapies designed to restore protein quality or protect mitochondria as alternate pathways to interrupt the disease process.
"Although much more work is needed before these discoveries can be translated into clinical treatments, we believe they provide a strong scientific foundation for an entirely new therapeutic strategy," Cann said.
The study was supported by the Japan Science and Technology Agency, the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, the Takeda Science Foundation, the Japan Association for Diabetes Education and Care, the Eli Lilly Japan Innovation Research Grant, the Daiwa Security Foundation and the Charles and Margaret Levin Family Foundation.