Ross River virus (RRV) is an Alphavirus distributed throughout Australia. It is transmitted by
mosquitoes and is known to cause moderate to severe disease symptoms in humans. Along with
other alphaviruses such as Sindbis virus and Chikungunya virus, RRV is known to cause arthritic
symptoms, characterised by muscle and joint inflammation. Several investigations have established
the role of macrophage cells and pro-inflammatory host factors in the development of RRV-induced
disease.
In this study, we attempted to determine differences between RRV passaged in mammalian and
mosquito cells. There is strong evidence that arthropod-borne viruses are able to display enhanced
infectivity when passaged into arthropod cell line. We showed that mosquito cell-derived RRV
(mos-RRV) was able to replicate to higher titres than mammalian cell-derived RRV. We also
showed that mos-RRV failed to induce Type I IFN-associated antiviral responses.
The second aim of this study was to investigate the role of TNF-ᬠa pro-inflammatory cytokine
implicated in arthritic diseases, in the development of RRV disease. We treated RRV-infected
C57BL/6J mice with a commercially available TNF-ᠩnhibitor drug and monitored disease signs.
We found that the TNF-ᠩnhibitor does not ameliorate RRV disease (RRVD) symptoms, and that it
does not prevent muscle and joint inflammation. We analysed histological sections of muscle and
joint tissue of Enbrel-treated and untreated, RRV-infected cells. We also determined and compared
host cytokine expression profiles.
Finally, we sought to determine the requirement for natural killer (NK) cells in RRV disease. NK
cells have been detected in the synovium of RRV-infected patients since early studies, but their role
in disease pathogenesis remains unclear. Using a NK-dysfunctional mouse (C57BL/6J-Lystbg), we
showed that mice lacking a functional NK system are more susceptible to RRV disease than wildtype,
C57BL/6J mice. We monitored disease symptoms following RRV infection and assessed
muscle and joint inflammation in Lystbg and C57BL/6J mice.
This thesis examines mechanisms of viral infection and immune evasion employed by RRV, as well
as into the role of host cells and cytokines in RRVD pathogenesis disease mechanisms. We showed
that a functional NK cell system is required for the regulation of RRV-induced muscle and joint
inflammation. Our characterisation of the use of a commercial TNF-ᠩnhibitor in RRV-induced
disease in mice may provide information on the role of TNF-ᠩn viral arthritis, and may help
towards developing safe and effective treatment.
| Identifer | oai:union.ndltd.org:ADTP/258933 |
| Date | January 2008 |
| Creators | Zaid, Ali, n/a |
| Publisher | University of Canberra. Biomedical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | ), Copyright Ali Zaid |
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