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Duo of membrane-slicing fungal proteins linked to respiratory allergies
Last reviewed: 09.08.2025
Scientists at the National Institute of Biological Sciences in Beijing report that two pore-forming proteins from the common mold Alternaria alternata puncture airway epithelial membranes and trigger signals that lead to allergic airway inflammation.
Allergens that trigger type 2 immunity—such as dust mites, pollen, and mold spores—are structurally similar to one another. Pattern-recognition receptors deal with bacterial and viral threats, while type 2 responses appear to detect tissue damage.
The MAPK signaling pathway acts as a molecular switchboard inside epithelial cells, translating external stress into gene-level commands. The cytokine IL-33 is an “alarm signal” that is normally stored in the nuclei of airway cells but is suddenly released when membranes are damaged, recruiting innate immune cells and directing a response. In allergic airway inflammation, MAPK activity amplifies the programs initiated by IL-33, placing both of these molecular components at the center of the inflammatory process.
In the study, “Epithelial cell membrane perforation induces allergic airway inflammation,” published in Nature, the scientists developed a strategy to purify and recreate the system to test whether fungal proteins could trigger type 2 inflammation through epithelial recognition mechanisms.
Human lung epithelial cell lines and repeated intranasal administration of proteins to mice were used as experimental models, monitoring early activation by IL-33 release, MAPK phosphorylation and inflammation-related gene expression.
The researchers found two proteins from the mold Alternaria alternata, called Aeg-S and Aeg-L, that work together to puncture the membranes of airway cells. Microscopic images show them linked together in a ring-shaped “drill” structure. At low doses, calcium enters the cells and triggers the MAPK cascade; at higher concentrations, the cells break down and release the “alarm” IL-33. Neither protein is active alone.
Blocking calcium entry or inhibiting the MAPK cascade completely stops all subsequent reactions. Inhaling a pair of proteins in mice causes classic signs of allergy: accumulation of eosinophils in the lungs, activation of T-helper 2 cells, and a sharp increase in IgE levels, while mold lacking one of the proteins does not provoke inflammation of the respiratory tract.
Six structurally unrelated pore-forming toxins—from fungi, bacteria, annelids, and cnidarians—induced similar changes in epithelial and immune responses when inhaled, including IL-33 release and MAPK activation in epithelial cells even without IL-33 feedback.
The findings suggest that membrane perforation is recognized by the body as a danger signal and is sufficient to trigger type 2 immune pathways in the airway epithelium. The authors suggest that many seemingly unrelated allergens and venoms contain pore-forming proteins, and that perforation may explain why such diverse stimuli cause similar airway inflammation.