Ross River virus envelope glycans contribute to disease through activation of the host complement system

Bronwyn M Gunn; Jennifer E Jones; Reed S Shabman; Alan C Whitmore; Sanjay Sarkar; Lance K Blevins; Thomas E Morrison; Mark T Heise

doi:10.1016/j.virol.2017.12.022

Ross River virus envelope glycans contribute to disease through activation of the host complement system

Virology. 2018 Feb:515:250-260. doi: 10.1016/j.virol.2017.12.022. Epub 2018 Jan 8.

Authors

Bronwyn M Gunn¹, Jennifer E Jones², Reed S Shabman³, Alan C Whitmore⁴, Sanjay Sarkar⁵, Lance K Blevins⁶, Thomas E Morrison⁷, Mark T Heise⁸

Affiliations

¹ Dept. of Microbiology and Immunology, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA. Electronic address: bgunn@mgh.harvard.edu.
² Dept. of Microbiology and Immunology, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA. Electronic address: jejxyz@email.unc.edu.
³ Dept. of Microbiology and Immunology, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA.
⁴ Dept. of Genetics, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA. Electronic address: alan_whitmore@med.unc.edu.
⁵ Dept. of Genetics, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA. Electronic address: sanjay_sarkar@med.unc.edu.
⁶ Dept. of Genetics, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA.
⁷ Dept. of Microbiology, University of Colorado School of Medicine, 12800 E. 19th Ave., RC1N 9119, Mail Stop 8333, Aurora, CO 80045, USA. Electronic address: thomas.morrison@ucdenver.edu.
⁸ Dept. of Microbiology and Immunology, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA; Dept. of Genetics, University of North Carolina at Chapel Hill, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599, USA. Electronic address: mark_heisem@med.unc.edu.

Abstract

Mannose binding lectin (MBL) generally plays a protective role during viral infection, yet MBL-mediated complement activation promotes Ross River virus (RRV)-induced inflammatory tissue destruction, contributing to arthritis and myositis. As MBL binds to carbohydrates, we hypothesized that N-linked glycans on the RRV envelope glycoproteins act as ligands for MBL. Using a panel of RRV mutants lacking the envelope N-linked glycans, we found that MBL deposition onto infected cells was dependent on the E2 glycans. Moreover, the glycan-deficient viruses exhibited reduced disease and tissue damage in a mouse model of RRV-induced myositis compared to wild-type RRV, despite similar viral load and inflammatory infiltrates within the skeletal muscle. Instead, the reduced disease induced by glycan-deficient viruses was linked to decreased MBL deposition and complement activation within inflamed tissues. These results demonstrate that the viral N-linked glycans promote MBL deposition and complement activation onto RRV-infected cells, contributing to the development of RRV-induced myositis.

Keywords: Alphavirus; Complement; Mannose-binding lectin; N-linked glycan; Ross River virus.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alphavirus Infections / immunology*
Alphavirus Infections / virology
Animals
Complement Activation
Complement System Proteins / immunology*
Disease Models, Animal
Humans
Mannose-Binding Lectin / immunology
Mice, Inbred C57BL
Polysaccharides / chemistry
Polysaccharides / immunology*
Ross River virus / genetics
Ross River virus / immunology*
Viral Envelope Proteins / chemistry
Viral Envelope Proteins / genetics
Viral Envelope Proteins / immunology*

Substances

Mannose-Binding Lectin
Polysaccharides
Viral Envelope Proteins
Complement System Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding