Despite improved antifungal agents, invasive Aspergillus fumigatus lung infections cause high morbidity and mortality in immunocompromised patients, for instance, in patients with therapy related neutropenia. In these dismal situations granulocyte transfusions have been tested as an alternative therapy for the management of high-risk neutropenic patients with invasive fungal infections. To increase the granulocyte yield for transfusion, donors are treated with corticosteroids. Yet, the efficacy of granulocyte transfusion and functional defense mechanisms of granulocytes collected from corticosteroid treated donors remain elusive.
We have used a combination of in vivo murine models and in vitro experiments to determine the efficacy granulocytes collected from corticosteroid treated donors to control invasive A. fumigatus infections.
Results and Conclusion:
Here we show that transfusion of granulocytes from corticosteroid treated mice did not protect immunosuppressed mice against lethal A. fumigatus infection in contrast to granulocytes from untreated donors. To study effects of corticosteroids on granulocyte antifungal defense functions we employed a corticosteroid treated A. fumigatus infection model. Upon infection increased levels of inflammatory cytokines helped to recruit neutrophilic granulocytes to the lungs of corticosteroid treated mice. Yet, after corticosteroid treatment, neutrophils failed to form neutrophil extracellular traps (NETs) against A. fumigatus. Corticosteroids impaired ROS production against A. fumigatus, which is also important for NET formation. Importantly, corticosteroids impaired the β-glucan receptor Dectin-1 (CLEC7A) on neutrophils to efficiently recognize and phagocytize A. fumigatus, which markedly impaired fungal killing. Collectively, our data indicate that corticosteroid treatment of granulocyte donors for increasing neutrophil yields could result in deleterious effects on neutrophil antifungal functions, thereby limiting the benefit of neutrophil transfusion therapies against invasive fungal infections. However, we also demonstrate that transfusion with CD11b+ myeloid cells collected from corticosteroid treated donors protect immunosuppressed mice against A. fumigatus infection.