The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection

PLoS Pathogens

Gregory L. Stahl¹  Thomas Dudler¹  Yuichi Endo²  Soren Hansen²  Youssif M. Ali³  Cordula M. Stover³  Wilhelm J. Schwaeble³  Russell Wallis³  Teizo Fujita³  Aras Kadioglu³  Peter W. Andrew³  Kashif S. Haleem³  Nicholas J. Lynch⁴  Kazue Takahashi⁵  Uffe Holmskov⁵  Umakhanth V. Girija⁶ 

[1] Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Immunology, Fukushima Medical University, Fukushima, Japan;Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom;Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt;Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark;Omeros Corporation, Seattle, Washington, United States of America

关键词: Pneumococcus;    Lectins;    Blood;    Complement activation;    Complement system;    Opsonization;    Mouse models;    Streptococcal infections;   

DOI  :  10.1371/journal.ppat.1002793

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.

【 授权许可】

CC BY