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Infection and Immunity, August 2008, p. 3429-3438, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.01510-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Aspergillus fumigatus Stimulates Leukocyte Adhesion Molecules and Cytokine Production by Endothelial Cells In Vitro and during Invasive Pulmonary Disease{triangledown}

Lisa Y. Chiang,1* Donald C. Sheppard,2 Fabrice N. Gravelat,2 Thomas F. Patterson,3 and Scott G. Filler1,4

Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California,1 Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada,2 University of Texas Health Science Center at San Antonio, San Antonio, Texas,3 The David Geffen School of Medicine at UCLA, Los Angeles, California4

Received 13 November 2007/ Returned for modification 25 December 2007/ Accepted 13 May 2008

Invasive aspergillosis is characterized by hyphal invasion of the blood vessels, which contributes to the pathogenesis of this disease. During this angioinvasion, Aspergillus fumigatus interacts with the endothelial cell lining of the blood vessels. We investigated the response of vascular endothelial cells to A. fumigatus infection in vitro and in mouse models of invasive pulmonary aspergillosis. Infection with hyphae, but not with conidia, stimulated endothelial cells to synthesize E-selectin, vascular cell adhesion molecule 1 (VCAM-1), interleukin 8, and tumor necrosis factor alpha (TNF-{alpha}) in vitro. Killed hyphae induced approximately 40% less stimulation than did live hyphae. Endothelial cell stimulation required contact between the hyphae and endothelial cells but not endocytosis of the organisms. Studies with {Delta}gliP and {Delta}stuA null mutants of A. fumigatus indicated that the extent of endothelial cell stimulation was not influenced by gliotoxin or other StuA-dependent factors synthesized by A. fumigatus. In neutropenic mice infected with wild-type A. fumigatus, increased pulmonary expression of E-selectin, cytokine-induced neutrophil chemoattractant (KC), and TNF-{alpha} occurred only when neutropenia had resolved. In nonneutropenic mice immunosuppressed with corticosteroids, A. fumigatus stimulated earlier pulmonary expression of E-selectin, VCAM-1, and KC, while expression of intercellular adhesion molecule 1 and TNF-{alpha} was suppressed. In both mouse models, expression of E-selectin and KC was associated with high pulmonary fungal burden, angioinvasion, and neutrophil adherence to endothelial cells. Therefore, the expression of leukocyte adhesion molecules and secretion of proinflammatory cytokines by endothelial cells in response to A. fumigatus could enhance the host defense against this organism by contributing to the recruitment of activated leukocytes to sites of angioinvasion.

* Corresponding author. Mailing address: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502. Phone: (310) 222-3813. Fax: (310) 782-2016. E-mail: lchiang{at}labiomed.org

{triangledown} Published ahead of print on 19 May 2008.

Editor: A. Casadevall

Infection and Immunity, August 2008, p. 3429-3438, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.01510-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bellanger, A.-P., Millon, L., Khoufache, K., Rivollet, D., Bieche, I., Laurendeau, I., Vidaud, M., Botterel, F., Bretagne, S. (2009). Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549. J Med Microbiol 58: 174-179 [Abstract] [Full Text]  


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