Postpartum innate responses and control of viral replication Pubblico

Abstract

The hepatitis C virus (HCV) persists in 75% of infected individuals, predisposing to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Following childbirth, however, women persistently infected with HCV may experience a significant decrease in plasma viral load or even clear infection. This work explores factors that may contribute to the postpartum decrease in viral load. We focus on interferon signaling in innate immune cells and the contributions of genetic polymorphisms. In addition, we report the use of the Cas9 RNA-guided endonuclease platform derived from prokaryotes to restrict HCV infection. Together these data highlight the complementary forces of the immune system and antivirals in the control of HCV.

Table of Contents

Distribution Agreement. I 

Approval Sheet. II 

Abstract Cover Page. III 

Abstract. IV 

Cover Page. V   

Acknowledgements. VI 

Table of Contents. VII-IX 

List of Figures and Tables. X-XI 

Chapter 1: An introduction to hepatitis C virus, pregnancy, and viral control. 1

Hepatitis C virus. 2

HCV epidemiology and global impact. 2

Viral life cycle. 3

HCV model systems. 5 

In vitro. 5 

In vivo. 6

HCV therapeutics: past, present, and future. 6

The immune response to HCV. 10 

Innate immunity. 10  

Interferons. 10  

Impact of genetic polymorphisms on the outcome of infection. 11  

Innate immune cells. 12

Adaptive immunity. 13  

Humoral immunity. 13 

T-cell mediated immunity. 14 

Pregnancy and the postpartum period in healthy women. 15

Placental anatomy and physiology. 15

Tolerance of the semi-allogeneic fetus. 16

Parturition and the postpartum period. 17 

HCV infection during pregnancy and following parturition. 18

Viral load dynamics. 19

Vertical transmission. 20 

References. 22

Figures and Figure legends. 34 

Chapter 2: Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype. 35

Abstract. 37

Significance. 38

Introduction. 39

Results. 40

Discussion. 45

Materials and Methods. 49

Acknowledgements. 53

References. 54

Figures and Figure legends. 59 

Chapter 3: Harnessing the prokaryotic adaptive immune system as a eukaryotic antiviral defense. 64

Abstract. 66

The prokaryotic immune system. 67

Cas9-mediated inhibition of eukaryotic viruses. 69

Cas9 targeting of RNA. 82

Obstacles to the use of Cas9 as an antiviral in humans. 84

Concluding remarks. 86

Acknowledgements. 88

References. 89

Figures and Figure legends. 101

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Molecular Biology, Virology Biology, Microbiology
Parola chiave	postpartum hepatitis C virus interferon signaling Cas9
Committee Chair / Thesis Advisor	Grakoui, Arash, Emory University
Committee Members	Evavold, Brian, Emory University Weiss, David S, Emory University Speck, Sam, Emory University Jacob, Joshy, Emory University

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