Mimicking evolution to define mechanisms of airborne transmission of H7N9 viruses

Project: Research project

Project Details

Description

The Asian lineage H7N9 avian influenza viruses (AIV) have caused >1500 human zoonotic infections with 615 deaths since 2013. These viruses have not spread in humans; however, there is a high potential for these viruses to evolve to transmit via the airborne route and cause a pandemic. A switch in receptor-binding preference in the viral hemagglutinin (HA) from ?2,3 to ?2,6-linked sialic acids is considered a requirement for airborne transmission. However, using ferrets as one of the best models to study transmission dynamics, we previously generated an airborne transmissible H7N1 AIV that did not have mutations to promote binding to ?2,6-linked sialic acids. More recently, we have evaluated the ability of the prototypic Asian lineage virus, A/Anhui/1/2013 (H7N9), to undergo two continuous rounds of airborne transmission. In these studies, we found that the virus displayed the ability to transmit to 50-66% of respiratory contact ferrets during both rounds of airborne transmission. In a subsequent deep sequence analysis, we identified 2-5 mutations in 90-99% of all variant viruses that transmitted. One mutation in the viral HA is known to promote strong binding to ?2,3-linked sialic acids, while additional mutations were found in the viral neuraminidase (NA) and polymerase genes. Therefore, we hypothesize that airborne transmission of H7N9 influenza does not require a distinct switch in receptor-binding preference, and that the virus will compensate for this lack of switching by acquiring mutations or reassortant gene segments to enhance the activity of the viral polymerase and NA genes. To address this hypothesis, our aims are: Aim 1. Determine the relative contribution of identified mutations to efficient airborne transmission of H7N9 influenza. In preliminary studies, HA mutations were rapidly selected followed by mutations in the NA and polymerase genes. Thus, viruses encoding combinations of these mutations will be evaluated for transmission in ferrets. Aim 2. Evaluate the role of mutations in the H7 HA on the selection of airborne transmissible H7N9-H1N1 reassortant viruses over two continuous rounds of transmission. Using reverse genetics, we will generate pools of H7N9-H1N1 reassortant viruses without the H1 HA to ensure generation of an H7 virus. Pools of these viruses with or without mutations in the H7 HA will then be used to initiate two continuous rounds of airborne transmission in ferrets. Viruses isolated from contact animals will be deep-sequenced and recombinant viruses carrying the minimal combination of gene segments that commonly reassort will be evaluated for transmission. In both aims, in vitro assays will be performed to determine the biological changes imparted by point mutations or reassortment. Collectively, these studies will determine both the amino acid changes and reassortment events that promote airborne transmission of H7N9 influenza viruses. Our findings will generate new insight and hypotheses on how AIV evolve to transmit via the airborne route and will yield critical knowledge required to interpret the evolution and assess the pandemic potential of H7N9 viruses.
StatusActive
Effective start/end date9/2/218/31/22

Funding

  • National Institute of Allergy and Infectious Diseases: $226,169.00

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