Mannose binding lectin is required for alphavirus-induced arthritis/myositis

Bronwyn Gunn, Thomas Morrison, Alan Whitmore, Lance Blevins, Linda Hueston, Robert Fraser, Lara Herrero, Paul Smith, Suresh Mahalingam, Mark Heise

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalPLoS Pathogens
Volume8
Issue number3
DOIs
Publication statusPublished - 2012

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Ross River virus
Alphavirus
Mannose-Binding Lectin
Myositis
Arthritis
Virus Diseases
Classical Complement Pathway
Alternative Complement Pathway
Complement Activation
Chikungunya virus
Pathology
Virus Activation
Muscles
Wild Animals
Synovial Fluid
Culicidae
Serum

Cite this

Gunn, B., Morrison, T., Whitmore, A., Blevins, L., Hueston, L., Fraser, R., ... Heise, M. (2012). Mannose binding lectin is required for alphavirus-induced arthritis/myositis. PLoS Pathogens, 8(3), 1-14. https://doi.org/10.1371/journal.ppat.1002586
Gunn, Bronwyn ; Morrison, Thomas ; Whitmore, Alan ; Blevins, Lance ; Hueston, Linda ; Fraser, Robert ; Herrero, Lara ; Smith, Paul ; Mahalingam, Suresh ; Heise, Mark. / Mannose binding lectin is required for alphavirus-induced arthritis/myositis. In: PLoS Pathogens. 2012 ; Vol. 8, No. 3. pp. 1-14.
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Gunn, B, Morrison, T, Whitmore, A, Blevins, L, Hueston, L, Fraser, R, Herrero, L, Smith, P, Mahalingam, S & Heise, M 2012, 'Mannose binding lectin is required for alphavirus-induced arthritis/myositis', PLoS Pathogens, vol. 8, no. 3, pp. 1-14. https://doi.org/10.1371/journal.ppat.1002586

Mannose binding lectin is required for alphavirus-induced arthritis/myositis. / Gunn, Bronwyn; Morrison, Thomas; Whitmore, Alan; Blevins, Lance; Hueston, Linda; Fraser, Robert; Herrero, Lara; Smith, Paul; Mahalingam, Suresh; Heise, Mark.

In: PLoS Pathogens, Vol. 8, No. 3, 2012, p. 1-14.

Research output: Contribution to journalArticle

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T1 - Mannose binding lectin is required for alphavirus-induced arthritis/myositis

AU - Gunn, Bronwyn

AU - Morrison, Thomas

AU - Whitmore, Alan

AU - Blevins, Lance

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AU - Fraser, Robert

AU - Herrero, Lara

AU - Smith, Paul

AU - Mahalingam, Suresh

AU - Heise, Mark

PY - 2012

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AB - 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.

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Gunn B, Morrison T, Whitmore A, Blevins L, Hueston L, Fraser R et al. Mannose binding lectin is required for alphavirus-induced arthritis/myositis. PLoS Pathogens. 2012;8(3):1-14. https://doi.org/10.1371/journal.ppat.1002586