Host Defense Against Aspergillosis in the p47phox-/- Mouse Model of Chronic Granulomatous Disease (CGD).

Z. BHATTI 1, C. G. DENNIS 1, J. FEMINELLA 1, Y. BRUN 1, N. G. ALMYROUDIS 1, R. LEWIS 2, S. M. HOLLAND 3, R. PETRAITIENE 4, T. J. WALSH 4, B. H. SEGAL1;

Author address: 

1Roswell Park Cancer Inst., Buffalo, NY, 2Univ. of Houston Coll. of Pharmacy, Houston, TX, 3Lab. of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, 4Pediatric Oncology Branch, NCI, NIH, Bethesda, MD.

Abstract: 

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.
2006

abstract No: 

M-1683

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th