title: Mannose binding lectin is required for alphavirus-induced arthritis/myositis.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Bronwyn M
authors.initials: BM
authors.lastname: Gunn
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
authors.forename: Alan C
authors.initials: AC
authors.lastname: Whitmore
authors.forename: Lance K
authors.initials: LK
authors.lastname: Blevins
authors.forename: Linda
authors.initials: L
authors.lastname: Hueston
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fraser
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Herrero
authors.forename: Ruben
authors.initials: R
authors.lastname: Ramirez
authors.forename: Paul N
authors.initials: PN
authors.lastname: Smith
authors.forename: Suresh
authors.initials: S
authors.lastname: Mahalingam
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
mesh_terms: D018354:Alphavirus Infections / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016918:Arthritis, Reactive / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003167:Complement Activation; D004195:Disease Models, Animal; D006801:Humans; D037601:Mannose-Binding Lectin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009220:Myositis / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D012398:Ross River virus / Q000472:pathogenicity / Q000502:physiology*; D013582:Synovial Fluid / Q000378:metabolism; D014779:Virus Replication
chemical_list: D037601:Mannose-Binding Lectin