Regulation of Ebolavirus Surface Glycoprotein Expression and its Role in Infection and Host Immune Evasion Open Access

Mohan, Gopi Sankarankovil (2015)

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The Ebola virus (EBOV) is the etiologic agent of Ebola Hemorrhagic Fever (EHF), a highly lethal disease with up to 90% mortality. There are currently no approved vaccines or antivirals for treatment of EBOV infection. While great strides have been made over the last two decades, our ability to treat and prevent EBOV hinges on expanding our understanding of EBOV biology and the mechanisms by which the virus induces such severe disease while evading host immunity. The EBOV surface glycoprotein (GP1,2), which mediates host cell attachment and fusion and is also the primary target of host antibodies, is a central player in the pathogenesis of EHF. The work presented in this dissertation examines regulation of glycoprotein expression by EBOV as it pertains to host immune evasion and virus infectivity - two primary determinants of viral fitness.

Table of Contents

Abstract. ii

Acknowledgements. iv

Table of Contents. v

List of Figures and Tables. vi

Abbreviations. vii

Chapter 1: Introduction. 1

Epidemiology, transmission, and threat of pandemic. 1

Structure, Biology, and the Surface Glycoprotein. 2

RNA Editing and Secreted Glycoproteins. 4

The Mucin Domain and Glycan Shielding. 9

Immunosuppressive Domain. 12

Tetherin Antagonism. 13

Implications for Vaccine Design. 15

Chapter 2: Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by the Ebola Virus. 18

Abstract. 19

Author Summary. 20

Introduction. 21

Materials and Methods. 24

Results. 29

Discussion. 37

Figures. 44

Chapter 3: Ebola Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity. 63

Abstract. 64

Introduction. 65

Materials and Methods. 69

Results. 73

Discussion. 83

Figures. 89

Chapter 4: Discussion and Future Directions. 105

Defining the Relevance of Antigenic Subversion to EHF Pathogenesis. 106

Choosing a Target: How Antigenic Subversion May Impact Ebola Vaccine Design. 107

How do GP1,2 Expression Levels Regulate Virus Fitness?. 110

Figures. 113

Works Cited. 115

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