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Aspergillus fumigatus Induces Innate Immune Responses in Alveolar Macrophages through the MAPK Pathway Independently of TLR2 and TLR4¹

Marc Dubourdeau^*, Rafika Athman, Viviane Balloy, Michel Huerre, Michel Chignard, Dana J. Philpott, Jean-Paul Latgé^* and Oumaïma Ibrahim-Granet^2,*

^* Unité des Aspergillus, Groupe Immunité Innée et Signalisation, Unité de Défense Innée et Inflammation, Institut National de la Santé et de la Recherche Médicale E336, and Unité de Recherche et d’Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France

Aspergillus fumigatus causes invasive aspergillosis in immunosuppressed patients. In the immunocompetent host, inhaled conidia are cleared by alveolar macrophages. The signaling pathways of the alveolar macrophage involved in the clearance of A. fumigatus are poorly understood. Therefore, we investigated the role of TLRs in the immune response against A. fumigatus and their contribution to the signaling events triggered in murine alveolar macrophages upon infection with A. fumigatus conidia. Specifically, we examined the MAPKs and NF-B activation and cytokine signaling. Our investigations revealed that immunocompetent TLR2, TLR4, and MyD88 knockout mice were not more susceptible to invasive aspergillosis as compared with wild-type mice and that the in vitro phosphorylation of the MAPKs ERK and p38 was not affected in TLR2, TLR4, or MyD88 knockout mice following stimulation with conidia. In vivo experiments suggest that ERK was an essential MAPK in the defense against A. fumigatus, whereas the activation of NF-B appeared to play only a secondary role. In conclusion, our findings demonstrate that TLR2/4 recognition and MyD88 signaling are dispensable for the clearance of A. fumigatus under immunocompetent situations. Furthermore, our data stress the important role of ERK activation in innate immunity to A. fumigatus.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Institut Pasteur provided financial support for this study through the Programme Transversal de Recherche, "A. fumigatus and the Alveolar Macrophage." M.D. and R.A. were supported by postdoctoral fellowships from Institut Pasteur.

² Address correspondence and reprint requests to Dr. Oumaïma Ibrahim-Granet, Institut Pasteur, Unité des Aspergillus, 25 Rue du Dr. Roux, 75724 Paris, Cedex 15, France. E-mail address: ogranet{at}pasteur.fr

³ Abbreviations used in this paper: AM, alveolar macrophage; BAL, bronchoalveolar lavage; MAM, murine AM; MKP, MAPK phosphatase.

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