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Infection and Immunity, March 2008, p. 952-958, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.00927-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MyD88 Signaling Contributes to Early Pulmonary Responses to Aspergillus fumigatus{triangledown}

Camille Bretz,1 Geoff Gersuk,1 Sue Knoblaugh,1 Neelkamal Chaudhary,3 Julie Randolph-Habecker,1 Robert C. Hackman,1,2 Janet Staab,1,3 and Kieren A. Marr1,2,3*

Fred Hutchinson Cancer Research Center, Seattle, Washington,1 University of Washington Medical Center,2 Oregon Health and Science University, Portland, Oregon3

Received 6 July 2007/ Returned for modification 19 July 2007/ Accepted 11 November 2007

Toll-like receptors and the β-glucan receptor, dectin-1, mediate macrophage inflammatory responses to Aspergillus fumigatus through MyD88-dependent and -independent signaling mechanisms; however, pulmonary inflammatory responses in MyD88-deficient mice challenged with A. fumigatus are poorly defined. The role of MyD88 signaling in early pulmonary inflammation and fungal clearance was evaluated in C57BL/6J wild-type (WT) and MyD88-deficient (MyD88–/–) mice. Early (<48 h) after infection, MyD88–/– mice had higher fungal burdens than those of WT mice, although fungal burdens rapidly declined (>72 h) in both. MyD88–/– mice had less consolidated inflammation, with fewer NK cells, in lung tissue early (24 h) after infection than did WT mice. At the latter time point, MyD88–/– mouse lungs were characterized by a large amount of necrotic cellular debris and fibrin, while WT lungs had organized inflammation. Although there were equivalent numbers of macrophages in WT and MyD88–/– mouse lung tissues, MyD88–/– cells demonstrated delayed uptake of green fluorescent protein-expressing A. fumigatus (GFP-Af293); histologically, MyD88–/– mouse lungs had more hyphal invasion of terminal airways and vessels, the appearance of bronchiolar epithelial cell necrosis, and necrotizing vasculitis. MyD88–/– lung homogenates contained comparatively decreased amounts of interleukin-1β (IL-1β), IL-6, KC, and gamma interferon and paradoxically increased amounts of tumor necrosis factor alpha and macrophage inflammatory protein 1{alpha}. These data indicate that the MyD88-dependent pathway mediates acute pulmonary fungal clearance, inflammation, and tissue injury very early after infection. Resolution of abnormalities within a 3-day window demonstrates the importance of redundant signaling pathways in mediating pulmonary inflammatory responses to fungi.

* Corresponding author. Mailing address: Oregon Health and Science University, Division of Infectious Diseases, 3181 SW Sam Jackson Park Rd., Mail Code NRC-03, Portland, OR 97239. Phone: (503) 418-1685. Fax: (503) 494-4264. E-mail: marrki{at}ohsu.edu

{triangledown} Published ahead of print on 26 November 2007.

Editor: A. Casadevall

Infection and Immunity, March 2008, p. 952-958, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.00927-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Ramaprakash, H., Ito, T., Standiford, T. J., Kunkel, S. L., Hogaboam, C. M. (2009). Toll-Like Receptor 9 Modulates Immune Responses to Aspergillus fumigatus Conidia in Immunodeficient and Allergic Mice. Infect. Immun. 77: 108-119 [Abstract] [Full Text]  


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