The modulation of autophagy by African swine fever virus

Shimmon, Gareth (2019) The modulation of autophagy by African swine fever virus. Doctoral thesis, University of East Anglia.

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Abstract

African swine fever (ASF) is a lethal haemorrhagic disease of domestic pigs caused by infection with African swine fever virus (ASFV). An outbreak in Russia in 2007 has since advanced into Europe and the Far East. With the spread of ASF expected to continue, the requirement for effective vaccines has become critical. The prospects for vaccine development are promising as infection with attenuated strains of ASFV can offer protection against closely related virulent strains.

Autophagy is an essential cell process that sequesters cytoplasmic cargo into double-membrane vesicles called autophagosomes for degradation via lysosomes. Autophagy regulates multiple pathways that are vital to mounting an effective immune response and viruses specifically target this pathway for modulation. Experiments have shown that inhibiting the ability of viruses to regulate autophagy can lead to enhanced immune responses. The work in this thesis shows that autophagy is actively inhibited by ASFV and is not required for virus replication. Further investigation revealed that ASFV activates Akt and mTORC1 which causes a block in autophagosome assembly. Pharmacological studies show that autophagy can be induced during the very early stages of viral replication but at later times, additional measures of modulation are implemented, most likely via virally encoded genes.

ASFV encodes A179L which binds to the key autophagy protein Beclin 1 leading to the inhibition of autophagosome formation. However, this work has demonstrated that additional protein modulators are also encoded. A gene library screen was conducted to identify these and unexpectedly, the results showed that some ASFV genes are able to stimulate elements of the autophagy pathway which was investigated further.

This research will expand our understanding of the interaction between ASFV and the autophagy pathway with the potential that a low virulent ASFV strain with an altered ability to modulate autophagy will provide enhanced immunity against virulent isolates.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Jennifer Whitaker
Date Deposited: 10 Mar 2020 16:33
Last Modified: 10 Mar 2020 16:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/74472
DOI:

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