Description du projet
Comprendre le tropisme du virus de la grippe
On a longtemps pensé que les hôtes aviaires constituaient le principal réservoir de tous les virus de la grippe A (IAV pour «influenza A virus»). Cette hypothèse est aujourd’hui remise en question par l’identification de deux nouveaux sous‑types de d’IAV chez les chauves‑souris: H17N10 et H18N11. Malgré un degré élevé d’homologie fonctionnelle avec les IAV conventionnels, les protéines de surface des IAV de chauve‑souris présentent plusieurs caractéristiques inédites. Le projet Bat Flu, financé par le CER, améliorera notre compréhension du tropisme des virus de la grippe. Plus précisément, il étudiera le mode d’interaction entre H17/H18 et CMH-II, et explorera le mécanisme de baisse de la régulation de CMH-II dépendant de N10/N11. Le projet Bat Flu explorera également la plasticité des IAV pour utiliser de nouveaux facteurs d’entrée cellulaires.
Objectif
Influenza A viruses (IAVs) are zoonotic pathogens that frequently cross the species barrier into humans, often causing severe morbidity and even global pandemics. This cross-species transmission is facilitated in large part by alterations in the interaction between the viral surface proteins hemagglutinin (HA) and neuraminidase (NA) and sialic acid, a ubiquitous glycan that serves as the cellular entry receptor. Although avian hosts have generally been thought to be the primary reservoir for all influenza A viruses, this dogma has recently been challenged by the identification of two novel IAV subtypes in bats, H17N10 and H18N11.
Despite an otherwise high degree of functional homology to conventional IAVs, the surface proteins of bat IAVs demonstrate several unprecedented characteristics. Specifically, these proteins are unable to interact with sialic acid; rather, we recently showed that bat IAVs use the major histocompatibility complex class II (MHC-II) protein to gain entry into host cells. Unexpectedly, we observed that N11 downregulates surface expression of MHC-II, suggesting that it potentially harbors a receptor-destroying function. Most surprisingly, bat IAV could replicate to even higher titers the absence of functional NA, a capability which has never been observed among influenza viruses.
These findings suggest that the surface glycoproteins of bat IAV may possess a structural plasticity that is much broader than that of conventional IAV. In light of the critical importance of the surface proteins for cross-species transmission of IAV, the goal of this project will be to probe this plasticity, first by determining the mode of interaction between H17/H18 and MHC-II and elucidating the mechanism of N10/N11-dependent downregulation of MHC-II, but most importantly by using forced evolution to explore the plasticity of IAV for new cellular entry factors. The insights from these studies will have a major impact on our understanding of influenza virus tropism.
Champ scientifique
- natural sciencesbiological sciencesmicrobiologyvirology
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza
- medical and health scienceshealth sciencespublic healthepidemiologyzoonosis
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
79106 Freiburg
Allemagne