The Beta-Glucan Receptor Dectin-1 Recognizes Specific Morphologies of Aspergillus fumigatus

PLoS Pathogens

Chad Steele¹  Rekha R Rapaka¹  Shannon M Pop¹  Jay K Kolls¹  Allison Metz¹  David L Williams²  Gordon D Brown³  Siamon Gordon⁴ 

[1] Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America;Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa;Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

关键词: Aspergillus fumigatus;    Alveolar macrophages;    Cytokines;    Chemokines;    Inflammation;    Toll-like receptors;    Macrophages;    Glucans;   

DOI  :  10.1371/journal.ppat.0010042

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Alveolar macrophages represent a first-line innate host defense mechanism for clearing inhaled Aspergillus fumigatus from the lungs, yet contradictory data exist as to which alveolar macrophage recognition receptor is critical for innate immunity to A. fumigatus. Acknowledging that the A. fumigatus cell wall contains a high beta-1,3–glucan content, we questioned whether the beta-glucan receptor dectin-1 played a role in this recognition process. Monoclonal antibody, soluble receptor, and competitive carbohydrate blockage indicated that the alveolar macrophage inflammatory response, specifically the production of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, CXCL2/macrophage inflammatory protein-2 (MIP-2), CCL3/macrophage inflammatory protein-1α (MIP-1α), granulocyte-colony stimulating factor (G-CSF), and granulocyte monocyte–CSF (GM-CSF), to live A. fumigatus was dependent on recognition via the beta-glucan receptor dectin-1. The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus. Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden, illustrating the importance of beta-glucan–initiated dectin-1 signaling in defense against this pathogen. Collectively, these data show that dectin-1 is centrally required for the generation of alveolar macrophage proinflammatory responses to A. fumigatus and to our knowledge provides the first in vivo evidence for the role of dectin-1 in fungal innate defense.

【 授权许可】

CC BY