Descrizione del progetto
Comprendere il tropismo del virus dell’influenza
Si è ritenuto a lungo che gli ospiti aviari fossero i bacini primari per tutti i virus dell’influenza A, ma ora l’ipotesi è messa in discussione dall’identificazione di due nuovi sottotipi nei pipistrelli: H17N10 e H18N11. Nonostante, per il resto, un elevato grado di omologia funzionale con i virus dell’influenza A convenzionali, le proteine di superficie dei virus nei pipistrelli mostrano diverse caratteristiche senza precedenti. Il progetto Bat Flu, finanziato dall’UE, migliorerà la nostra comprensione del tropismo del virus dell’influenza, studiando, nello specifico, la modalità di interazione tra H17/H18 e MHC-II ed esaminando il meccanismo di sottoregolazione N10/N11-dipendente di MHC-II. Il progetto Bat Flu esplorerà inoltre la plasticità dei virus dell’influenza A per l’utilizzo di nuovi fattori di ingresso cellulari.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
79106 Freiburg
Germania