Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis

Area of Science:

• Immunology
• Mycology
• Systems Biology

Background:

• Effective anti-Aspergillus immunity relies on the integration of innate and adaptive immune responses.
• While inflammation is crucial for protection, excessive inflammation can exacerbate disease and hinder pathogen clearance.
• Dendritic cells (DCs) play a pivotal role in initiating immune responses by sensing pathogens and activating distinct signaling pathways.

Purpose of the Study:

• To elucidate the molecular pathways governing pathogenic inflammation during Aspergillus infection.
• To investigate how distinct sensing mechanisms by lung DCs differentiate responses to fungal conidia and hyphae.
• To explore the potential of targeting DC signaling pathways for therapeutic intervention in respiratory fungal diseases.

Main Methods:

• Utilized a systems biology approach to screen signaling pathways in dendritic cells (DCs) in vitro.
• Investigated the in vivo immune responses triggered by conidia and hyphae.
• Employed intranasally delivered small interfering RNA (siRNA) to target specific DC pathways, including PI3K/Akt/mTOR and STAT3/IDO.

Main Results:

• Distinct intracellular pathways in lung DCs mediate the sensing of Aspergillus conidia versus hyphae.
• Conidia sensing by DCs activates protective Th1/Treg responses, while hyphae sensing induces inflammatory Th2/Th17 responses.
• In vivo targeting of inflammatory (PI3K/Akt/mTOR) or anti-inflammatory (STAT3/IDO) DC pathways with siRNA modulated inflammation and immunity.

Conclusions:

• Dendritic cell signaling pathways differentially regulate immune responses to Aspergillus fungal forms.
• Targeting these DC pathways offers a strategy to control inflammation in respiratory fungal infections.
• Systems biology screening of DC signaling pathways can inform the development of siRNA therapeutics for fungal diseases.