Host-Specific Production of Gliotoxin (GT) and Bis-methyl-gliotoxin (bmGT) During Invasive Aspergillosis (IA)

S. R. Rose, J. A. Sugui, G. A. Nardone, J. K. Kwon-Chung, M. S. Lionakis; NIH, Bethesda, MD


Background: IA causes high mortality in immunosuppressed hosts, in part due to suboptimal diagnosis. GT and bmGT are Aspergillus metabolites produced during invasive hyphal growth and may be useful diagnostic markers for IA. As the pathophysiology of IA and GT's role in virulence vary greatly by host risk factor, we hypothesized that GT and bmGT production is distinct in the 3 mouse models of IA that mimic human IA pathogenesis: chronic granulomatous disease (CGD), steroid-induced and neutropenia. Methods: Phox p47-/- CGD and wild type (WT) mice were infected intrapharyngeally with A. fumigatus [LD80 by day 10 post-infection (pi) in all 3 models]. WT mice were given subQ hydrocortisone (HC; 2 mg at days -4, -2, 0, +2, +4) or were rendered neutropenic by mGr-1 injection IP (100 μg 16 hrs before infection). Serum, bronchoalveolar lavage fluid (BALF) and lung homogenates were used for measuring GT and bmGT by HPLC at days 1, 3 and 5 pi (n=4-6/time-point). Lungs were used for H&E and GMS staining. Results: (Figure) GT lung levels were significantly greater in neutropenic mice. GT peaked at day 3 pi when mice were profoundly neutropenic, consonant with extensive pulmonary hyphal invasion, and declined by day 5 pi upon neutrophil recovery. bmGT was only transiently detected in neutropenic lung, was not detected in HC-treated lung and was persistently seen only in CGD lung. GT, but not bmGT, was detected in 71% of sera (mean, 65.8 ng/mL) and 50% of BALF (mean, 18.6 ng/mL) of neutropenic mice; neither GT nor bmGT was detected in serum or BALF of CGD or HC-treated mice. Conclusions: GT, but not bmGT, is detectable at high concentrations in mouse lung, serum and BALF specifically during neutropenic IA. These data suggest that GT may be useful for diagnosis of IA in neutropenic patients.


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Full conference title: 

54th Interscience Conference of Antimicrobial Agents and Chemotherapy
    • ICAAC 54th (2014)