Descripción del proyecto
Comprender el tropismo de los virus de la gripe
Hace mucho que se piensa que los hospedadores aviares son el principal reservorio de todos los virus de la gripe A (VGA). Esto se ha puesto ahora en entredicho con la identificación de dos nuevos subtipos de VGA en los murciélagos: el H17N10 y el H18N11. A pesar de tener un alto grado de homología funcional con los VGA convencionales, las proteínas de superficie de los VGA de murciélago muestran varias características sin precedentes. El proyecto Bat Flu, financiado por el Consejo Europeo de Investigación, mejorará nuestra comprensión del tropismo de los virus de la gripe. Concretamente, estudiará la forma de interacción entre H17/H18 y el complejo mayor de histocompatibilidad de clase II e investigará el mecanismo de regulación a la baja dependiente de N10/N11 del complejo principal de histocompatibilidad de clase II. El proyecto Bat Flu también investigará la plasticidad de los VGA para utilizar nuevos factores de entrada celular.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
79106 Freiburg
Alemania