Clinical determinants of macrophage necrosis in pulmonary aspergillosis

Pulmonary aspergillosis is an opportunistic infection that affects 30% of adults with cystic fibrosis. Our studies show that calcineurin signalling regulates macrophage cell death during Aspergillus fumigatus infection and it is excessive in cystic fibrosis. Furthermore, cystic fibrosis isolates of Aspergillus fumigatus have enhanced pH and cell wall tolerance, suggesting macrophage adaptation. My goals are to determine if clinical Aspergillus fumigatus isolates induce higher rates of macrophage cell death, and if patients with cystic fibrosis have exaggerated macrophage cell death responses to infection.

We will define the necrotic potential of clinical strains of Aspergillus fumigatus. Patients with cystic fibrosis patients and environmental isolates will be compared for their ability to induce human macrophage necrosis in vitro. We will characterise Aspergillus-dependent macrophage necrosis in cystic fibrosis. Macrophages from patients with cystic fibrosis and control patients will be compared for their ability to induce programmed necrosis during Aspergillus infection. We will also define the role of macrophage cell death in vivo. Cystic fibrosis and environmental isolates will be compared for their ability to induce macrophage necrosis in vivo in murine pulmonary aspergillosis.

These studies will determine whether macrophage cell death responses to Aspergillus fumigatus are influenced by fungal strain phenotype and host immunity in cystic fibrosis.