How influenza pandemics get started
H5, H7, and H9 avian influenza subtypes top the World Health Organization’s list of strains with the greatest pandemic potential. A transition from avian-like 2,3-linked sialic acid (SA2,3) receptors to human-like 2,6-linked sialic acid (SA2,6) receptors appears to be a crucial step for avian influenza viruses to replicate efficiently and transmit in humans. An increasing number of contemporary avian H9N2 viruses contain leucine (L) at position 226 in the hemagglutinin (HA) receptor-binding site (RBS), supporting the preferential binding to SA2,6 receptors and the ability to replicate efficiently in human respiratory epithelial cells and in the ferret model, an in vivo model which closely resembles human airway epithelium and clinical infection. Since the mid-1990’s, H9N2 influenza viruses have become endemic in poultry throughout Eurasia and have occasionally transmitted to humans and pigs. In addition to possessing human virus-like receptor specificity, avian H9N2 viruses induce typical human flu-like illness, which can easily go unreported, and therefore have the opportunity to circulate, undergo reassortment, and increase in transmissibility.
Seroepidemiological studies in Asia suggest that the incidence of human H9N2 infections could be more prevalent than what has been reported and possible human-to-human transmission cannot be completely excluded. These direct infections with avian H9N2 confirm that interspecies transmission of H9N2 from avian species to mammalian hosts occurs and it is not uncommon. Reassortment between the current human epidemic strain and an avian virus of a different subtype is postulated to generate the next pandemic strain. Given the receptor specificity of avian H9N2 viruses and their repeated introduction into humans, as recent as December 2008, the opportunity for their reassortment and/or adaptation for human-to-human transmission is ever present. However the question remains what is missing for the H9N2 virus to transmit from human-to-human and possibly lead to the next pandemic.
A new study describes respiratory droplet transmission of an avian–human H9N2 influenza virus in ferrets and pinpoints the minimal changes necessary for respiratory droplet transmission in this model. After only 10 passages of nasal washes researchers were able to establish infection and sustain respiratory droplet transmission that was reproducible in multiple studies. This adaptation required only 5 amino acid changes in the entire influenza virus genome, implying that little is needed for currently circulating avian H9N2 viruses to transmit human-to-human following reassortment with a human strain. Studies to identify the minimal changes necessary indicated three changes in the surface HA and NA as the key point mutations essential for respiratory droplet transmission. The scientists also identified and located a change that dramatically alters the antigenicity of the virus, bringing to light the inherent limitations in the selection of vaccine seed stocks for avian H9N2 viruses and the possible inefficiency regarding the seed stock selection of other avian influenza strains. Whether these changes can affect transmission phenotypes of additional avian H9N2 strains and possibly other influenza subtypes, most notably H5 and H7, remains to be determined.
Minimal molecular constraints for respiratory droplet transmission of an avian–human H9N2 influenza A virus. PNAS USA April 20, 2009
Pandemic influenza requires interspecies transmission of an influenza virus with a novel hemagglutinin (HA) subtytpe that can adapt to its new host through either reassortment or point mutations and transmit by aerosolized respiratory droplets. Two previous pandemics of 1957 and 1968 resulted from the reassortment of low pathogenic avian viruses and human subtypes of that period; however, conditions leading to a pandemic virus are still poorly understood. Given the endemic situation of avian H9N2 influenza with human-like receptor specificity in Eurasia and its occasional transmission to humans and pigs, we wanted to determine whether an avian–human H9N2 reassortant could gain respiratory transmission in a mammalian animal model, the ferret. Here we show that following adaptation in the ferret, a reassortant virus carrying the surface proteins of an avian H9N2 in a human H3N2 backbone can transmit efficiently via respiratory droplets, creating a clinical infection similar to human influenza infections. Minimal changes at the protein level were found in this virus capable of respiratory droplet transmission. A reassortant virus expressing only the HA and neuraminidase (NA) of the ferret-adapted virus was able to account for the transmissibility, suggesting that currently circulating avian H9N2 viruses require little adaptation in mammals following acquisition of all human virus internal genes through reassortment. Hemagglutinin inhibition (HI) analysis showed changes in the antigenic profile of the virus, which carries profound implications for vaccine seed stock preparation against avian H9N2 influenza. This report illustrates that aerosolized respiratory transmission is not exclusive to current human H1, H2, and H3 influenza subtypes.
Related:
- The Biology of Influenza
- Influenza pandemic – when?
- The Pathogenicity of Pandemic Influenza Viruses
- H5N1 and 1918 pandemic influenza virus infection and the lungs
Tags: Biology, Emerging disease, Health, Influenza, Medicine, Microbiology, pandemic, Science, Vaccines, Virology
