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Infection and Immunity, January 2005, p. 114-125, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.114-125.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Pathogenesis of Fatal Outcome in Murine Pulmonary Aspergillosis Depends on the Neutrophil Depletion Strategy

Shane D. Stephens-Romero,1,{dagger} Aron J. Mednick,1,{dagger} and Marta Feldmesser1,2,3*

Division of Infectious Diseases, Department of Medicine,1 Department of Microbiology & Immunology,2 Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York3

Received 18 August 2004/ Returned for modification 2 September 2004/ Accepted 10 September 2004

Aspergillus fumigatus causes invasive disease in severely immunocompromised hosts but is readily cleared when host innate defenses are intact. Animal models for evaluation of therapeutic strategies to combat invasive aspergillosis that closely mimic human disease are desirable. We determined optimal dosing regimens for neutrophil depletion and evaluated the course of infection following aerosol infection in mice by determining survival, organ fungal burden, and histopathology in mice in which neutropenia was induced by three methods, administration of granulocyte-depleting monoclonal antibody RB6-8C5 (MAb RB6), administration of cyclophosphamide, and administration of both agents. Administration of either individual agent resulted in a requirement for relatively high conidial inocula to achieve 100% mortality in both BALB/c and C57BL/6 mice, although the infection appeared to be somewhat more lethal in C57BL/6 mice. Death following induction of neutropenia with MAb RB6 occurred when a relatively low fungal burden was present in the lung and may have been related to the inflammatory response associated with neutrophil recovery. In contrast, administration of both agents reduced the lethal inoculum in each mouse strain by approximately 1 log10, and C57BL/6 mice that received both agents had a higher fungal burden and less inflammation in the lung at the time of death than BALB/c mice or mice of either strain that received MAb RB6 alone. Our data suggest that the relationship among fungal burden, inflammation, and death is complex and can be influenced by the immunosuppression regimen, the mouse strain, and the inoculum.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, Forchheimer Building, Room 402, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-3487. Fax: (718) 430-8968. E-mail: feldmess{at}aecom.yu.edu.

Editor: T. R. Kozel

{dagger} S.D.S.-R. and A.J.M. contributed equally to this study.

Infection and Immunity, January 2005, p. 114-125, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.114-125.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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