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Nature. 2019 Mar;567(7746):109-112. doi: 10.1038/s41586-019-0955-3. Epub 2019 Feb 20.

MHC class II proteins mediate cross-species entry of bat influenza viruses.

Author information

1
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
2
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.
3
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4
Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
5
Faculty of Biology, University of Freiburg, Freiburg, Germany.
6
Department of Microsystems Engineering - IMTEK, University of Freiburg, Freiburg, Germany.
7
Institute of Diagnostic Virology, Friedrich-Loeffler Institut, Greifswald-Insel Riems, Germany.
8
Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler Institut, Greifswald-Insel Riems, Germany.
9
Helmholtz Pioneer Campus, Helmholtz Zentrum Munich, Neuherberg, Germany.
10
Department of Medicine, University of California, San Diego, CA, USA.
11
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
12
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
14
Division of Virology, Institute of Virology and Immunology, Mittelhäusern, Switzerland.
15
Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
16
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
17
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany. martin.schwemmle@uniklinik-freiburg.de.
18
Faculty of Medicine, University of Freiburg, Freiburg, Germany. martin.schwemmle@uniklinik-freiburg.de.
19
Institute of Medical Virology, University of Zurich, Zurich, Switzerland. stertz.silke@virology.uzh.ch.

Abstract

Zoonotic influenza A viruses of avian origin can cause severe disease in individuals, or even global pandemics, and thus pose a threat to human populations. Waterfowl and shorebirds are believed to be the reservoir for all influenza A viruses, but this has recently been challenged by the identification of novel influenza A viruses in bats1,2. The major bat influenza A virus envelope glycoprotein, haemagglutinin, does not bind the canonical influenza A virus receptor, sialic acid or any other glycan1,3,4, despite its high sequence and structural homology with conventional haemagglutinins. This functionally uncharacterized plasticity of the bat influenza A virus haemagglutinin means the tropism and zoonotic potential of these viruses has not been fully determined. Here we show, using transcriptomic profiling of susceptible versus non-susceptible cells in combination with genome-wide CRISPR-Cas9 screening, that the major histocompatibility complex class II (MHC-II) human leukocyte antigen DR isotype (HLA-DR) is an essential entry determinant for bat influenza A viruses. Genetic ablation of the HLA-DR α-chain rendered cells resistant to infection by bat influenza A virus, whereas ectopic expression of the HLA-DR complex in non-susceptible cells conferred susceptibility. Expression of MHC-II from different bat species, pigs, mice or chickens also conferred susceptibility to infection. Notably, the infection of mice with bat influenza A virus resulted in robust virus replication in the upper respiratory tract, whereas mice deficient for MHC-II were resistant. Collectively, our data identify MHC-II as a crucial entry mediator for bat influenza A viruses in multiple species, which permits a broad vertebrate tropism.

PMID:
30787439
DOI:
10.1038/s41586-019-0955-3

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