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

Bronwyn M Gunn,Lance K Blevins,Lara J Herrero,Alan C Whitmore,Mark T Heise,Ruben Ramirez,Suresh Mahalingam,Linda Hueston,Thomas E Morrison,Robert J Fraser,Paul N Smith

doi:10.1371/journal.ppat.1002586

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.

Highlights

Arthritogenic alphaviruses, such as Ross River virus (RRV) and chikungunya virus (CHIKV), are mosquito-borne viruses that cause severe polyarthritis and myositis in humans
Complement activation products are elevated in the synovial fluid of persons suffering from RRV-induced arthritis and complement activation is required for virus-induced arthritis/ myositis in a mouse model [8,9,20]
In contrast to C1q2/2 and fB2/2 mice, mannose binding lectin (MBL)-DKO mice infected with RRV developed mild hind-limb weakness and exhibited reduced weight loss compared to WT mice (Figure 1, A and B)

Summary

Introduction

Arthritogenic alphaviruses, such as Ross River virus (RRV) and chikungunya virus (CHIKV), are mosquito-borne viruses that cause severe polyarthritis and myositis in humans. The expansion of CHIKV into an additional mosquito vector and the subsequent epidemic has highlighted the ability of the arthritic alphaviruses to move into new geographic areas and cause large-scale outbreaks of acute and persistent arthralgia and myalgia in humans. RRV-induced arthritic disease presents predominantly as painful stiffness, inflammation, and swelling in peripheral joints that can last months after initial infection and the host inflammatory response is thought to play a major role in disease pathogenesis. Inflammatory monocytes constitute the bulk of leukocytes isolated in synovial aspirates from RRV-infected patients [4,5], and macrophage-cytotoxic drugs have been shown to drastically reduce disease progression and severity in mice [6,7]. Mice lacking C3, the central complement factor that is essential for complement activation, exhibit reduced RRVinduced disease and tissue destruction [8], implicating a role for Author Summary

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