The viral determinants of alphavirus-induced rheumatic disease have not been elucidated. We identified an RRV strain (DC5692) which, in contrast to the T48 strain, does not induce musculoskeletal inflammation in a mouse model of RRV disease. Substitution of the RRV T48 strain nonstructural protein 1 (nsP1) coding sequence with that from strain DC5692 generated a virus that was attenuated in vivo despite similar viral loads in tissues. In contrast, substitution of the T48 PE2 coding region with the PE2 coding region from DC5692 resulted in attenuation in vivo and reduced viral loads in tissues. In gain of virulence experiments, substitution of the DC5692 strain nsP1 and PE2 coding regions with those from the T48 strain was sufficient to restore full virulence to the DC5692 strain. These findings indicate that determinants in both nsP1 and PE2 have critical and distinct roles in the pathogenesis of RRV-induced musculoskeletal inflammatory disease in mice.
Bibliographical noteFunding Information:
This research was supported by NIH research grant K22 AI079163 awarded to T.E.M. and R01 AR047190 awarded to M.T.H. We thank Drs. Cheryl Johansen and David Smith (University of Western Australia) who were instrumental in the isolation of RRV strain DC5692 from mosquitoes.
Copyright 2011 Elsevier B.V., All rights reserved.
- Rheumatic disease