HMN 2025: How Membrane drilling mold protein duo is implicated in airway allergies

Scientists at the National Institute of Biological Sciences, Beijing report that two pore-forming proteins from the common mold Alternaria alternata puncture airway epithelial membranes and initiate signals that drive allergic airway inflammation.

Allergens that provoke type 2 immunity such as dust mites, pollen, and mold spores share little structural similarity. Pattern-recognition receptors handle bacterial and viral threats, while type 2 responses appear to detect tissue disruption instead.

MAPK signaling works like a molecular switchboard inside epithelial cells, turning outside stress into gene-level commands. IL-33 is an alarm signal cytokine that normally stays tucked inside airway-cell nuclei but surges out when membranes break, rallying innate immune cells and steering a response. In allergic airways, MAPK activity amplifies the programs started by IL-33, so both molecules sit at the center of inflammation.

In the study, “Epithelial cell membrane perforation induces allergic airway inflammation,” published in Nature, researchers designed a purification-and-reconstitution strategy to test whether fungal proteins can initiate type 2 inflammation through epithelial sensing.

Human lung epithelial cell lines and repeated intranasal protein exposure in mice served as the experimental systems, with early activation tracked through IL-33 release, MAPK phosphorylation, and inflammatory-gene expression.

Scientists uncovered two mold proteins from Alternaria alternata, Aeg-S and Aeg-L, that team up to pierce airway-cell membranes. Images show them connected as a ring-shaped drill. Low exposure lets calcium rush inside and flips on a MAPK relay. Heavier exposure bursts the cells and releases the alarm signal IL-33. Each protein is produced with no effect alone.

Blocking calcium entry or the MAPK relay was enough to stop every downstream response. Breathing in the duo drives classic allergy signs in mice, with eosinophils in the lungs, T-helper-2 cells, and surging IgE, while mold engineered to lack either protein leaves airways calm.

Six structurally unrelated pore-forming toxins from fungi, bacteria, annelids, and cnidarians provoked similar epithelial and immune features upon airway exposure, including IL-33 release and MAPK activation in epithelial cells even without IL-33 feedback.

Study data indicate that membrane perforation registers as danger and is sufficient to launch type 2 immune pathways in the airway epithelium. The authors argue that many otherwise unrelated allergens and venoms carry pore-forming proteins, so perforation may explain why diverse stimuli provoke similar airway inflammation.

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