Autor(es)Taylor Adam, Melton Julian V, Herrero Lara J, Thaa Bastian, Karo-Astover Liis, Gage Peter W, Nelson Michelle A, Sheng Kuo-Ching, Lidbury Brett A, Ewart Gary D, McInerney Gerald M, Merits Andres, Mahalingam Suresh

ResumoThe alphaviral 6k region encodes the two structural proteins 6K protein -, due to a ribosomal frameshift event, TF protein. Here, we characterized the role of the 6k proteins in the arthritogenic alphavirus Ross River virus (RRV) in infected cells - in mice, using a novel 6k in-frame deletion mutant. Comprehensive microscopic analysis revealed that the 6k proteins were predominantly localized at the endoplasmic reticulum of RRV-infected cells. RRV virions that lack the 6k proteins were more vulnerable to changes in pH - corresponding virus had increased sensitivity to higher temperature. While the 6k deletion did not reduce RRV particle production in BHK-21 cells, it affected virion release from the host cell. Subsequent in vivo studies demonstrated that RRV-(?6K) caused a milder disease than wild-type virus, with reduced viral titres in infected mice. Immunisation of mice with RRV-(?6K) resulted in reduced viral load - accelerated viral elimination upon secondary infection with WT-RRV or another alphavirus, chikungunya virus (CHIKV). Our results show that the 6k proteins may contribute to alphaviral disease manifestations - suggest that manipulating the 6k gene may be a potential strategy to facilitate viral vaccine development. Arthritogenic alphaviruses such as chikungunya virus (CHIKV) - Ross River virus (RRV) cause epidemics of debilitating rheumatic disease in endemic areas - can emerge in new regions worldwide. RRV is of considerable medical significance in Australia, where it is the leading cause of arboviral disease. The mechanisms by which alphaviruses persist - cause disease in the host are ill-defined. This paper describes the phenotypic properties of an RRV 6k-deletion mutant. The absence of the 6k gene reduced virion release from infected cells - also reduced the severity of disease - viral titres in infected mice. Immunisation with the mutant virus protected mice against viraemia not only upon exposure to RRV, but also upon challenge with CHIKV. These findings could lead to the development of safer - more immunogenic alphavirus vectors for vaccine delivery.

ImprentaJournal of Virology, v. 90, n. 8, p. 4150-4159, 2016

DescritoresChikungunya virus - Cell ; Chikungunya virus - Genome ; Chikungunya virus - Proteins ; Chikungunya virus - Inflammation ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Epidemic

Data de Publicação:2016