The development of a reverse genetics system for the study of chikungunya pathogenesis in the mouse model


Chamberlain, JF; (2015) The development of a reverse genetics system for the study of chikungunya pathogenesis in the mouse model. PhD thesis, London School of Hygiene & Tropical Medicine. DOI: 10.17037/PUBS.02305377

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Abstract

The genus Alphavirus is one of two within the family Togaviridae and comprises approximately 30 species, including several pathogens of humans and other animals that are of medical, veterinary and economic importance. Most alphaviruses are maintained in nature by a biological transmission cycle between susceptible vertebrate hosts and blood-feeding arthropods such as mosquitoes. In common with many Old World alphavirus pathogens Chikungunya virus (CHIKV) is the aetiological agent of a syndrome characterized by fever, skin rash and acute or chronic poly-arthralgia or arthritis. Whereas previously CHIKV outbreaks were sporadic and self-limiting, in 2004 it re-emerged in coastal Kenya and there followed a series of outbreaks that have continued until the present day, resulting in many millions of cases. Inroads into understanding the pathogenesis of CHIKV disease were until recently hampered through the lack of a convenient small animal model capable of exhibiting symptoms similar to those observed in humans in response to viral challenge. By contrast, studies with other alphaviruses, most notably Sindbis and Semliki Forest viruses (SINV and SFV), have provided insights into many aspects of the infectious process including several key determinants of virulence. In the present study a reverse genetics system was developed to investigate the pathogenesis of CHIKV disease, the virus replication cycle and its interactions with susceptible hosts. This tool was used to investigate the hypothesis that a CHIKV encoded virulence factor is located within the cleavage domain of the non-structural polyprotein precursor of the viral replicase. Results from this study indicate that a unique amino acid within this conserved site is instrumental in contributing the inhibition of the type 1 IFN response in infected hosts. It was also shown that the type 1 IFN response was induced at an earlier stage in mice challenged with virus containing an engineered mutation at this site and that joint-swelling was less severe than with wild-type virus.

Item Type: Thesis
Thesis Type: Doctoral
Thesis Name: PhD
Contributors: Raynes, Jg (Thesis advisor); Hewson, R (Thesis advisor);
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Faculty of Infectious and Tropical Diseases
Research Group: Virology & Pathogenesis Group, Public Health England, Porton Down
Funders: Health Protection Agency, National Institute of Health Research, Centre for Health Protection Research
Copyright Holders: John Chamberlain
URI: http://researchonline.lshtm.ac.uk/id/eprint/2305377

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