Calcium signaling pathway is involved in non-CYP51 azole resistance in Aspergillus fumigatus

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.