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Calcium signaling pathway is involved in non-CYP51 azole resistance in Aspergillus fumigatus
Yeqi Li1, Yuanwei Zhang1, Ling Lu1
1Jiangsu Key laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China.
Abstract:
The opportunistic fungal pathogen Aspergillus fumigatus, which is one of the primary airborne ascomycete pathogens and allergens worldwide, causes invasive fungal infections, which have high morbidity and mortality rates among immunosuppressed patients. The abuse of azole antifungals results in serious drug resistance in clinical therapy. Thus, a thorough understanding of the azole drug resistance mechanism and screening of antifungal agents with a novel mode of action and new drug targets are required to fight against drug resistance. Current studies suggest that there are three major azole resistance mechanisms in fungal pathogens, including changes of the drug target Cyp51, activation of drug efflux pumps and induction of cellular stress responses. Fungi must adapt to a variety of external environmental stressors to survive. These obstacles include stress to the plasma membrane after azole antifungal treatments, high temperature, pH variation, and oxidative stress. As a filamentous fungus, A. fumigatus has evolved numerous signal-transduction systems to sense and respond to azole stresses to survive and proliferate in harsh environmental conditions. Among these signal-transduction systems, the Ca2+ signaling pathway is one of the most important response systems, which has been verified to be involved in stress adaptation. In this review, we have summarized how the components of the calcium-signaling pathway and their interaction network are involved in azole stress response in A. fumigatus.
Insights
Investigating the calcium signaling pathway in Aspergillus fumigatus reveals its crucial role in adapting to azole antifungal drug resistance. Understanding this pathway is key to developing new treatments for invasive fungal infections.
Area of Science:
- Medical Mycology
- Molecular Biology
- Drug Resistance
Background:
- Aspergillus fumigatus is a major airborne fungal pathogen causing life-threatening infections in immunocompromised individuals.
- Azole antifungal drug resistance is a growing clinical problem, necessitating research into resistance mechanisms.
- Fungal pathogens must adapt to various environmental stressors, including those induced by antifungal treatments.
Purpose of the Study:
- To review the role of the calcium signaling pathway in Aspergillus fumigatus's response to azole antifungal stress.
- To elucidate the interaction network of calcium signaling components involved in azole stress adaptation.
- To identify potential new targets for antifungal drug development.
Main Methods:
- Literature review of studies on Aspergillus fumigatus, azole resistance, and calcium signaling.
- Analysis of signal-transduction systems involved in fungal stress response.
- Summary of current knowledge on azole resistance mechanisms (Cyp51 alterations, efflux pumps, stress responses).
Main Results:
- Calcium signaling is a critical pathway for Aspergillus fumigatus to adapt to azole stress.
- Specific components and their interactions within the calcium-signaling network mediate survival under azole pressure.
- Understanding these mechanisms is vital for combating drug-resistant fungal infections.
Conclusions:
- The calcium signaling pathway is integral to Aspergillus fumigatus's survival and proliferation under azole antifungal stress.
- Targeting components of this pathway may offer novel strategies to overcome azole resistance.
- Further research into the calcium-signaling network is essential for developing effective antifungal therapies.
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