The stability of influenza haemagglutinin and its significance for pathogenicity, transmission and control
File(s)
Author(s)
Singanayagam, Anika
Type
Thesis
Abstract
Influenza A viruses are highly diverse and predominantly exist in animal reservoirs. In the rare but significant event that an influenza virus acquires the capability to jump from animal to human host, a pandemic can result. The most recent example of this occurred in 2009 when the pandemic H1N1 (pH1N1) virus emerged from swine causing the first influenza pandemic of the 21st century. Over the subsequent decade, it has circulated as a human seasonal virus, causing further morbidity and mortality worldwide.
The ability of an influenza virus to infect and transmit between humans is multifactorial. In recent years, pH stability of the haemagglutinin (HA) surface protein has been realised as an important property associated with human adaptation and transmission. Understanding how pH stability impacts on virus/host interactions that support replication and transmission in humans is important for improving risk assessment of emerging viruses with pandemic potential.
In this study, recombinant influenza viruses with point mutations that alter the pH stability of pH1N1 HA were used to investigate the consequences of pH stability for pathogenicity and transmissibility. The data show that a stable HA is beneficial for virus infectivity in the mammalian upper respiratory tract, enabling virus to withstand the acidic environment. Conversely, entry into host cells via endosomal uncoating is facilitated by a HA that is less pH stable. A novel technique for isolating influenza virus directly from air exhaled by infected ferrets revealed that HA stability enhances virus survival in airborne droplets. However, using the same apparatus airborne virus was not isolated from human volunteers infected with pH1N1 virus.
Our findings indicate that different influenza viruses may show variation in how well they are controlled by antiviral strategies targeting pH-dependent steps in the virus replication cycle and how effective they are as part of nasally-administered live attenuated vaccines.
The ability of an influenza virus to infect and transmit between humans is multifactorial. In recent years, pH stability of the haemagglutinin (HA) surface protein has been realised as an important property associated with human adaptation and transmission. Understanding how pH stability impacts on virus/host interactions that support replication and transmission in humans is important for improving risk assessment of emerging viruses with pandemic potential.
In this study, recombinant influenza viruses with point mutations that alter the pH stability of pH1N1 HA were used to investigate the consequences of pH stability for pathogenicity and transmissibility. The data show that a stable HA is beneficial for virus infectivity in the mammalian upper respiratory tract, enabling virus to withstand the acidic environment. Conversely, entry into host cells via endosomal uncoating is facilitated by a HA that is less pH stable. A novel technique for isolating influenza virus directly from air exhaled by infected ferrets revealed that HA stability enhances virus survival in airborne droplets. However, using the same apparatus airborne virus was not isolated from human volunteers infected with pH1N1 virus.
Our findings indicate that different influenza viruses may show variation in how well they are controlled by antiviral strategies targeting pH-dependent steps in the virus replication cycle and how effective they are as part of nasally-administered live attenuated vaccines.
Version
Open Access
Date Issued
2019-10
Date Awarded
2020-06
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Barclay, Wendy
Sponsor
Wellcome Trust (London, England)
Grant Number
WT105736MA
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)