Abstract
Ross River fever is a mosquito-transmitted viral disease that is endemic to Australia and the surrounding Pacific Islands. Ross River virus (RRV) belongs to the arthritogenic group of alphaviruses, which largely cause disease characterized by debilitating polyarthritis, rash, and fever. There is no specific treatment or licensed vaccine available, and the mechanisms of protective humoral immunity in humans are poorly understood. Here, we describe naturally occurring human mAbs specific to RRV, isolated from subjects with a prior natural infection. These mAbs potently neutralize RRV infectivity in cell culture and block infection through multiple mechanisms, including prevention of viral attachment, entry, and fusion. Some of the most potently neutralizing mAbs inhibited binding of RRV to Mxra8, a recently discovered alpahvirus receptor. Epitope mapping studies identified the A and B domains of the RRV E2 protein as the major antigenic sites for the human neutralizing antibody response. In experiments in mice, these mAbs were protective against cinical disease and reduced viral burden in multiple tissues, suggesting a potential therapeutic use for humans.
Highlights
Ross River virus (RRV) is a positive-sense, single-stranded RNA virus in the Alphavirus genus of the Togaviridae family
A mean of 4,600 cases of RRV disease occur in Australia each year
We isolated a panel of moncoclonal antibodies (mAbs) from two subjects, one with a previous laboratory-confirmed case of RRV that was acquired in Australia in 1987, and the other with a clinical history of childhood infection in Australia in the 1990s
Summary
Ross River virus (RRV) is a positive-sense, single-stranded RNA virus in the Alphavirus genus of the Togaviridae family. RRV was first isolated from human serum using suckling mice in 1972, but was not connected with symptoms until large epidemics in the South Pacific islands in 1979–1980, in which approximately 70,000 people were infected [1,9,10]. Recent evidence indicates that other mammalian species such as rodents, rabbits, and flying foxes can act as reservoirs for the virus and contribute to its spread [12,13]. This finding suggests that RRV may have the potential to spread to regions outside of Australia and the Pacific Islands and raises concerns about future epidemic transmission. There are no approved vaccines or specific therapies targeting RRV
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