Project Overview

Project 3 - Pandemic flu; Host Adaptation of Influenza A Virus

Principal Investigator: Ron Fouchier, Ph.D.
Professor, Department of Virology
Erasmus Medical Center, Rotterdam, The Netherlands

Influenza Pandemic Chart

Influenza pandemics of the 20th century caused by avian-to-human transmission and adaptation in 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2).

Influenza A viruses have the remarkable property of infecting many different animal species, including birds (waterfowl, chickens, turkeys, et al.), horses, pigs and humans. Influenza pandemics occur when an influenza A virus for which we have not developed immunity is transmitted from an animal reservoir to humans and succeeds to spread globally. Recently, avian-to-human transmissions of H5N1 and H7N7 influenza A viruses have occurred relatively frequently but have not led to new pandemics, presumably because the avian viruses were incapable of efficient replication in humans or transmission between humans. Genetic mixing of avian and human influenza A viruses and accumulation of mutations are believed to yield viruses with enhanced replication and transmission properties in humans, but little direct evidence is available. The factors involved in the ability of an avian influenza virus strain or of a reassortant virus containing avian antigenic determinants to infect and propagate in humans are poorly understood. This lack of knowledge hampers our ability to predict the pandemic potential of avian influenza virus strains circulating in birds.

Mapping host adaptation in pandemic influenza. Our aim is to unravel the molecular basis for the emergence of pandemic influenza A viruses. We are investigating host-specific functions of influenza A virus proteins, interaction between viral components, and genome packaging requirements of influenza A virus, which could be key to the emergence of pandemic influenza. One focus is the emergence of pandemic influenza A viruses during the last two pandemics (1957 H2N2, 1968 H3N2) in the context of the genetic and phenotypic variability of avian, human, and porcine influenza A viruses. We are conducting extensive phylogenetic analyses to determine the “ancestral states” of the viruses responsible for the last 2 pandemics and will attempt to generate ancestral viruses through reverse genetics. Due to the low fidelity of the viral polymerase complex and the ability of gene reassortment, the genomes of influenza A viruses are highly variable. This genome plasticity is thought to be important for zoonotic events, the initiation of pandemics, and subsequent maintenance of endemicity in humans. We are evaluating the roles of HA, NA, and the polymerase proteins of pandemic and zoonotic influenza viruses in determining host-range and cross-species transmission of influenza viruses. Additional studies of packaging signals will map the regions in the viral genome that facilitate gene reassortment. Using experimental systems available to CRIP researchers, we will test the potential of gene reassortment between zoonotic and contemporary human influenza viruses and effects on transmission.

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