Charting the Host Adaptation of Influenza Viruses

Abstract

Four influenza pandemics have struck the human population during the last 100 years causing substantial morbidity and mortality. The pandemics were caused by the introduction of a new virus into the human population from an avian or swine host or through the mixing of virus segments from an animal host with a human virus to create a new reassortant subtype virus. Understanding which changes have contributed to the adaptation of the virus to the human host is essential in assessing the pandemic potential of current and future animal viruses. Here, we develop a measure of the level of adaptation of a given virus strain to a particular host. We show that adaptation to the human host has been gradual with a timescale of decades and that none of the virus proteins have yet achieved full adaptation to the selective constraints. When the measure is applied to historical data, our results indicate that the 1918 influenza virus had undergone a period of preadaptation prior to the 1918 pandemic. Yet, ancestral reconstruction of the avian virus that founded the classical swine and 1918 human influenza lineages shows no evidence that this virus was exceptionally preadapted to humans. These results indicate that adaptation to humans occurred following the initial host shift from birds to mammals, including a significant amount prior to 1918. The 2009 pandemic virus seems to have undergone preadaptation to human-like selective constraints during its period of circulation in swine. Ancestral reconstruction along the human virus tree indicates that mutations that have increased the adaptation of the virus have occurred preferentially along the trunk of the tree. The method should be helpful in assessing the potential of current viruses to found future epidemics or pandemics.

Reassortment and Mutation of the Avian Influenza Virus Polymerase PA Subunit Overcome Species Barriers

“…PA residue 552 has not been previously shown specifically to play an important role in polymerase function in experimental systems. However, it was identified by several computational strategies as a signature residue indicative of viral origin (4,8,11,46,48). It has also been shown to undergo characteristic "host shift" changes in amino acid identity as the selective pressures on this residue change from birds to humans (44).…”

“…Those with PA subunits from 2009 pH1N1 possessed the highest levels of activity. We mapped this enhancing activity in multiple seasonal influenza viruses to a single amino acid, PA amino acid 552, which was identified previously by bioinformatic analysis as a residue marking host shifts (4,8,11,46,48). Viruses created with these reassorted polymerases had enhanced replication kinetics in culture and enhanced pathogenicity in animal infections.…”

Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins

“…Upon mapping tolerated insertion sites, we identified two regions of the viral genome that were highly enriched for mutations. The identified regions were in domains associated with host adaptation and immune response evasion (10,11): the viral glycoprotein hemagglutinin (12,13) and nonstructural protein 1 (NS1) (14,15). These data suggest that although the majority of the viral genome is resistant to major mutation, two viral proteins contain extremely flexible proteins scaffolds.…”

The influence of changing host immunity on 1918–19 pandemic dynamics

“…Virological and genealogical studies of the 1918 pandemic virus, whilst based on limited genetic samples, imply that pH1N11918 had been circulating in mammals for several years prior to the pandemic, and likely co-circulated with seasonal and swine lineages of H1N1 (Smith et al, 2009;dos Reis et al, 2011). In more contemporary pandemics severe second waves of pandemic transmission may have been triggered by changes in the circulating virus (Viboud et al, 2005).…”