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.

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

“…[22][23][24] In addition, these studies have shown the importance of type I interferons and complement in mice. [25][26][27][28][29] In humans, overlap has been identified between persistent CHIKV and rheumatoid arthritis; and proinflammatory mediators seem to play a role in disease progression and persistence. [30][31][32][33] However, the study of ONNV has received relatively little attention since its discovery, though it was the cause of one of the largest known arboviral outbreaks in the late 1950s and early 1960s in Uganda.…”

Dendritic Cell Immunoreceptor Regulates Chikungunya Virus Pathogenesis in Mice

“…CLRs have been shown to enhance alphavirus and flavivirus infection of dendritic cells (18,36), and recent studies have implicated the CLR CLEC5A in promoting inflammatory pathology during both dengue virus and Japanese encephalitis virus infection (63,64). Furthermore, another lectin binding protein, mannose binding lectin, has been shown to play a major role in promoting virus-induced inflammatory disease during Ross River virus-induced myositis (65).…”

“…There is strong evidence that the host inflammatory response plays a pathological role during infection with CHIKV and other arthritic alphaviruses (34,36,47,52); however, the role that specific host factors play in modulating the CHIKV-induced inflammatory response is still poorly understood. A number of studies have found evidence that alphaviruses interact with C-type lectin receptors (CLRs) (36,39,40), and given that one of these receptors, DCIR, has been shown to regulate the severity of collagen-induced arthritis, we evaluated DCIR's role in the pathogenesis of CHIKVinduced disease.…”

“…High levels of proinflammatory cytokines in human patients and mice further implicate immune cells and their products in driving the tissue and joint pathology of CHIKV disease (29)(30)(31)(32). Finally, viral immunopathogenesis has been well characterized in other closely related alphaviruses, such as RRV (33)(34)(35)(36).…”

“…In vitro, mosquito cell-derived Sindbis virus (SINV) and Venezuelan equine encephalitis virus (VEE) have been shown to utilize dendritic cell (DC)-specific intercellular adhesion molecule-3-grabbing nonintegrin (SIGN) and liver-specific SIGN (L-SIGN) as attachment receptors on DCs; and RRV, Barmah Forest virus (BFV), and VEE differentially induced type I interferon (IFN) on the basis of the various glycosylation patterns between mosquito-and mammal-produced virus (37)(38)(39)(40). In vivo, specific alterations in the glycosylation pattern of SINV increased replication and virulence in mice (41), and the soluble CLR mannose binding lectin (MBL) was recently shown to promote RRV disease in both mice and humans (36).…”