Ross River Infection causes arthritis in humans and mice.

So, there haven't really been many pathogens discussed here so far, and I figured I'd write a little about a virus that's really unique in the way that your immune system clears it.

Ross River Virus (RRV), is a negative sense, enveloped, single stranded RNA virus in the family Togaviridae and was first isolated in 1959 from a mosquito in Australia. It is one of the members of the Old World alphaviruses, and symptoms in humans are usually a rash, followed 2 weeks or so later by various musculoskeletal symptoms in the extremities. These can include arthritis/arthralgia, as well as muscle pain. The interesting thing about these symptoms is that they do not go away in a matter of days as one would normally expect. They can instead persist for weeks to months, and in rare cases, years after infection. There are also currently no treatments, and no vaccine against this or any other arthritic alphavirus.

Figure 1. The Ross River is designated by the marker "A".

In comparison to encephalitic alphaviruses, very little is understood about arthritic disease cause by alphaviruses. It was not until 2006 that a mouse model of RRV infection was published. (Morrison et al, 2006) These preliminary studies showed that infection of mice with RRV resulted in massive inflammation of bone, joint, and skeletal muscle tissues in the hind limbs. Further analysis showed that the cells causing this inflammatory response were macrophages, NK cells, CD4+ and CD8+ lymphocytes. Current studies are looking at the which type of macrophage is involved, as well as how the virus is causing this massive immune response.

The greatest advantage to this model system is that the disease process in mice closely resembles that seen in humans, therefore, presumably, any advances made in understanding viral pathogenesis in the mouse can be transferred into the human disease with a fair amount of confidence.

Figure 2. Photograph of a patient infected with Ross River Virus.

As if that wasn't enough, an avirulent strain has been isolated which contains 45 amino acid substitutions when compared to the WT. This avirulent virus has been shown to replicate just as efficiently as the WT virus, however it does not induce any of the inflammation seen in WT RRV infection. Current studies on comparing these two genomes have identified 2 independent genetic virulence determinants in regions of the genome that contain only 11 AA changes. Site directed mutagenesis of each one of these 11 AA residues will hopefully identify 1 or 2 particular AA residues which are critical to viral pathogenesis.

Figure 3. Histology of Mouse quadriceps tissue. A. Mouse infected with wild type RRV. B. Mouse infected with avirulent strain of RRV. Both mice received the same amount of virus during infection.

The hope is that these virulence determinants might allow researchers to begin working on a possible therapeutic vaccine. The other hope is that these particular AA residues may be conserved across different species of alphaviruses such as Chikungunya and others, and that it might be possible to transfer any finding gleaned from RRV and incorporate them in the battle against Chikungunya. (If you're interested in reading about Chikungunya, feel free to check out: http://en.wikipedia.org/wiki/Chikungunya.)

References:

Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of arthritis and myositis.

Morrison TE, Whitmore AC, Shabman RS, Lidbury BA, Mahalingam S, and Heise MT.

Journal of Virology, 2006, 80(2):737-49.