Periodic Reporting for period 2 - Bat Flu (Deciphering the unconventional receptor binding and modulation activity of bat influenza A viruses)
Période du rapport: 2022-05-01 au 2023-10-31
In order to establish a robust binding assay for the viral hemagglutinin and MHC-II, which might pave the ground for the resolution of this interaction by crystallography or Cryo-EM, we expressed and purified high-quality H18 and MHC-II, respectively, and can now show a direct interaction of these two complexes by two independent biochemical binding methods.
We speculated that bat-derived IAV would induce clustering of MHC-II molecules on the host cell surface to provide sufficient avidity for viral entry. In order to challenge this hypothesis, we generated MHC-II molecules, which are labeled with a photoswitchable fluorophore. Using these labeled MHC-II molecules we can now show by high resolution microscopy that indeed the attachment of bad-derived IAV triggers MHC-II clustering and subsequent uptake.
Following the discovery of H17N10 and H18N11 in New World bat species, a distinct H9N2 IAV was isolated from Egyptian fruit bats in the Nile Delta region. In contrast to the New World bat IAVs, the bat H9N2 shares many characteristics of conventional IAVs, including the sialic acid receptor specificity required for cell entry. To address whether bat H9N2 is of zoonotic concern, we, together with our collaboration partners evaluated (i) the infection and transmission potential in ferrets, a commonly used animal model to mirror infection of humans, (ii) the ability to replicate in human lung explants, (iii) the escape from human MxA, a crucial innate antiviral factor for zoonotic IAVs, and (iv) antigenic novelty to the human population. This study demonstrates that bat H9N2 meets key characteristics of pre-pandemic IAVs and is available as a preprint (https://www.researchgate.net/publication/370972286_The_bat-borne_influenza_A_virus_H9N2_exhibits_a_set_of_unexpected_pre-pandemic_features).
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 882631).