Ross River study offers arthritis clues

Hundreds of Australians have endured misery and debilitating arthritic pain in the joints after being infected by mosquito-borne Ross River Virus. The symptoms can last for months, and recovered patients can relapse years later.

Ross River Virus (RRV) is native to Australia, and is maintained in the environment by marsupials. In humans it causes a syndrome of potentially chronic, debilitating disorders, including polyarthritis, where the patient's own immune cells appear to invade the joints, causing local disease.

A number of related viruses from other regions of the world cause similar, chronic arthritis-like infections, but the mechanism by which such viruses interacts with the immune system to bring "friendly fire" on the tissues is unclear.

Humans are not the only recent mammal newcomers to Australia who are susceptible to RRV. Dr Suresh Mahalingam, of the Infection and Immunity Group in Wollongong University's Department of Biological Sciences, who is collaborating with Dr Mark Heise (University of North Carolina) and Dr Brett Lidbury (University of Canberra) believe they have developed a good mouse model of RRV-induced arthritis - also known as epidemic polyarthritis.

They have constructed a Ross River virus carrying the jellyfish green fluorescent protein that they can use to track the virus' location, concentration and persistence in the mouse's cells and tissues - particularly in muscles and joints.)

The collaborators published a paper in Proceedings of the National Academy of Science (PNAS) that threw light onto how viruses may trigger enhanced early infection which may later contribute to arthritis.

Mahalingam and Lidbury have discovered that the autoimmune attack in Ross River disease involves a previously undescribed mechanism.

In last year's PNAS paper, they described how, after the virus complexes with antibodies, the virus-antibody complex then somehow influences the immune system to up-regulate the potent cytokine interleukin-10 (IL-10), which is a primary mechanism in the observed suppression of anti-viral defence molecules after infection.

The virus-antibody complexes are engulfed by macrophages, giant scavenger cells that sweep the body for bacteria and other biological detritus.

Mahalingam says that these virus-antibody complexes somehow suppress the expression of genes that mediate the immune system's anti-viral response, so Ross River virus then replicates to very high levels in the macrophage cells.

The increase in infectivity that occurs with the virus-antibody complex involves increased expression of IL-10, a natural suppressor of the anti-viral response.

Despite the discovery, Mahalingam says therapy for RRV-induced polyarthritis and similar forms of arthritis is probably a "long way down the track". The team hopes to receive NHMRC funding this year to continue this work.

"It's novel work, but our data suggests that the host's own cell-signalling factors, such as cytokines or chemokines, may be involved in suppressing the anti-viral response.

"Viral compounds may be capable of doing that as well, but we have no evidence for that yet. But we do have evidence that the virus-antibody complexes suppress the anti-viral response by up-regulating the anti-inflammatory cytokine IL-10, which also suppresses the anti-viral response."

He said one possible therapeutic avenue for virally induced arthritis might be a monoclonal antibody directed at selected chemokines or their receptors -- similar to the way in which anti-TNF-alpha antibody therapies like Remicade suppress rheumatoid arthritis.