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Deciphering the unconventional receptor binding and modulation activity of bat influenza A viruses

Objective

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.

Field of science

  • /natural sciences/biological sciences/microbiology/virology
  • /medical and health sciences/health sciences/epidemiology/pandemics
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/health sciences/infectious disease/RNA virus/influenza
  • /medical and health sciences/health sciences/epidemiology/zoonosis

Call for proposal

ERC-2019-ADG
See other projects for this call

Funding Scheme

ERC-ADG - Advanced Grant

Host institution

UNIVERSITAETSKLINIKUM FREIBURG
Address
Hugstetter Strasse 49
79106 Freiburg
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 499 637,50

Beneficiaries (1)

UNIVERSITAETSKLINIKUM FREIBURG
Germany
EU contribution
€ 2 499 637,50
Address
Hugstetter Strasse 49
79106 Freiburg
Activity type
Higher or Secondary Education Establishments