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Title: The role of the early secretory pathway in foot-and-mouth disease virus replication
Author: Midgley, Rebecca Julie
ISNI:       0000 0004 2705 1991
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Foot-and-Mouth Disease Virus (FMDV) induces rearrangements of host-cell membranes to generate vesicles that are believed to provide platforms for formation of the viral replication complex. The cellular origin of these vesicles and the properties that make them favourable for replication are poorly understood. For some Picornaviruses these vesicles are thought to derive from membranes of the secretory pathway. In this thesis, I have investigated a role for membranes of the secretory pathway in FMDV infection. Key cellular proteins involved in regulating the flow of membranes through the secretory pathway between the ER and Golgi were inhibited using expression of dominant-negative (dn) proteins and small interfering RNA (siRNA) and the effect on FMDV infection determined. Inhibition of ER export using a drug (H89) or Sar1 (the GTPase required for COPII transport vesicle formation at ER exit sites) reduced FMDV infection. In contrast, stabilisation of COPII coats, or inhibition of Arf1 or Rab proteins, that are involved in the secretory pathway after the formation of COPII vesicles, had little or no inhibitory effect on infection. Interestingly inhibition of Arf1, Rab1 or Rab2 enhanced infection. In contrast, Arf1 reduced infection by bovine enterovirus which is inhibited by Brefeldin-A, and therefore likely to be dependent on Arf1 for replication. These results show that Sar1 and/or COPII vesicle formation is necessary for FMDV infection and that inhibiting the formation of COPI coats is in some way advantageous to FMDV infection. These results suggest that FMDV targets COPII vesicles membranes before the COPII/COPI exchange and facilitates FMDV infection and that COPI components are not required.
Supervisor: Jackson, Terry ; Burman, Alison ; Goodfellow, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral