Background: CGD is a disorder of NADPH oxidase (NADPHO) characterized by severe bacterial and fungal infections. We used p47phox-/- (CGD) mice (M) to evaluate NADPHO-independent host defense against Aspergillus fumigatus (Af). Methods: Survival, histology, fungal burden, and cytokine responses were compared in these M: CGD alone, CGD + cyclophosphamide (Cy), CGD + anti-Gr1 neutrophil depleting antibody, wildtype (WT) + Cy, and WT + anti-Gr1. Results: Susceptibility to intratracheal (IT) Af (1.25 x 104 CFU) based on mortality was: CGD + Cy > CGD alone > WT + Cy. In separate studies, M were administered IT Af (1.25 x 104 CFU) and sacrificed on day 5. CGD alone M developed focal neutrophilic infiltrates surrounding hyphae, and no vascular invasion. CGD + Cy M developed acellular coagulative necrosis and hyphal angioinvasion. CGD + anti-Gr1 M, developed histiocytic infiltrates with few neutrophils and hyphal angioinvasion. WT + Cy and WT + anti-Gr1 mice had no invasive disease. Serum galactomannan (GM) was significantly increased in CGD + Cy M, likely reflecting high organism burden and vascular invasion. Bronchoalveolar lavage (BAL) GM was significantly increased in CGD + Cy and CGD + anti-Gr1 M compared to CGD alone. BAL TNF-alpha from CGD + Cy M was dramatically increased compared to CGD + anti-Gr1 and CGD alone. In subacute aspergillosis in CGD M 32 days after IT Af (2.5 x103 CFU), discrete predominantly neutrophilic granulomata and swollen and blebbed hyphal tips reflecting hyphal damage occurred. Conclusions: Host defense against Af in CGD M was defective but not nil based on the ability to contain infection, damage hyphae, and prevent vascular invasion. Further research will evaluate NADPHO-independent mechanisms intact in CGD that protect against Af.
Full conference title:
46th Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC 46th