Identification of Influenza Hemagglutinin Residues Critical for Membrane Fusion Activity Open Access

Abstract

Influenza is a major public health risk causing annual seasonal epidemics and sporadic pandemics when a subtype transmits to naïve human population and circulates.  Current vaccine strategies are limited, requiring annual immunization and evaluation of included strains. The hemagglutinin (HA), one of the major surface glycoproteins of influenza A virus, is the principle target for vaccination. HA functions in the viral life cycle both in the binding of the virus to host cells and in mediating fusion of the viral and endosomal membranes, via a low pH-induced conformational change.  The structural rearrangements of the HA during this conformational change are critical to viral entry, and mutations in the protein can impact the pH at which fusion occurs and the overall stability of the HA structure.  HA stability can play a role in viral pathogenesis, host range, and adaptation to new hosts.  The HA is expressed as a homotrimeric spike on viral surfaces, with a membrane-distal globular head domain situated on a fibrous stalk, or stem domain. Current vaccines focus immunity on the HA head, which undergoes frequent mutations during “antigenic drift”. The HA stalk is more conserved and therefore an attractive target for universal vaccine strategies and antiviral drug design. The 16 antigenic HA subtypes of naturally circulating influenza A viruses are segregated into two groups, group-1 and group-2. For the group-2 HAs, previous studies identified specific residues within the HA stalk as potential “trigger” residues for membrane fusion-associated conformational changes. However, for group-1 HAs no such residues have been conclusively implicated. Based on comparative sequence analyses and structural considerations, a series of experiments were designed to gain insights into the initiation of conformational changes for group-1 HAs.  Functional studies on mutant HAs of several subtypes revealed that a histidine at residue 111 within the HA2 subunit of group-1 HA types was required for acid-induced conformational changes and membrane fusion activity.  As this histidine is completely conserved in natural isolates of group-1 HAs, it might serve as an “Achilles’ heel” residue to target in future vaccine and antiviral strategies.

Table of Contents

Table of Contents

List of Figures and Tables

Introduction                                                                                                                           1

A Conserved Histidine in Group-1 Influenza subtype hemagglutinin proteins is essential for membrane fusion activity                                                                                              28

Conclusion, Discussion, and Future Directions                                                              60

References                                                                                                                           71

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Microbiology Biology, Molecular Biology, Virology
Keyword	Influenza Fusion
Committee Chair / Thesis Advisor	David Steinhauer, Emory University

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