Mannose Binding Lectin Is Required for Alphavirus-Induced Arthritis/Myositis

PLoS Pathogens

Robert J. Fraser¹  Lance K. Blevins²  Thomas E. Morrison²  Linda Hueston²  Lara J. Herrero³  Bronwyn M. Gunn⁴  Alan C. Whitmore⁵  Paul N. Smith⁶  Mark T. Heise⁷  Ruben Ramirez⁸  Suresh Mahalingam⁸ 

[1] Arbovirus Emerging Disease Unit, CIDMLS-ICPMR, Westmead Hospital, Westmead, Australia;Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia;Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America;Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, Australia;The Australian National University, Canberra, Australia;Virus and Inflammation Research Group, University of Canberra, Canberra, Australia

关键词: Complement activation;    Mouse models;    Inflammatory diseases;    Complement system;    Inflammation;    Muscle tissue;    Skeletal muscles;    Synovial fluid;   

DOI  :  10.1371/journal.ppat.1002586

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3−/− mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis.

【 授权许可】

CC BY