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

Umut Karakus, Thiprampai Thamamongood, Kevin Ciminski, Wei Ran, Sira C. Günther, Marie O. Pohl, Davide Eletto, Csaba Jeney, Donata Hoffmann, Sven Reiche, Jan Schinköthe, Reiner Ulrich, Julius Wiener, Michael G. B. Hayes, Max W. Chang, Annika Hunziker, Emilio Yángüez, Teresa Aydillo, Florian Krammer, Josua Oderbolz, Matthias Meier, Annette Oxenius, Anne Halenius, Gert Zimmer, Christopher Benner, Benjamin G. Hale, Adolfo García-Sastre, Martin Beer, Martin Schwemmle () and Silke Stertz ()
Additional contact information
Umut Karakus: University of Zurich
Thiprampai Thamamongood: Medical Center University of Freiburg
Kevin Ciminski: Medical Center University of Freiburg
Wei Ran: Medical Center University of Freiburg
Sira C. Günther: University of Zurich
Marie O. Pohl: University of Zurich
Davide Eletto: University of Zurich
Csaba Jeney: University of Freiburg
Donata Hoffmann: Friedrich-Loeffler Institut
Sven Reiche: Friedrich-Loeffler Institut
Jan Schinköthe: Friedrich-Loeffler Institut
Reiner Ulrich: Friedrich-Loeffler Institut
Julius Wiener: Helmholtz Zentrum Munich
Michael G. B. Hayes: University of California
Max W. Chang: University of California
Annika Hunziker: University of Zurich
Emilio Yángüez: University of Zurich
Teresa Aydillo: Icahn School of Medicine at Mount Sinai
Florian Krammer: Icahn School of Medicine at Mount Sinai
Josua Oderbolz: ETH Zurich
Matthias Meier: Helmholtz Zentrum Munich
Annette Oxenius: ETH Zurich
Anne Halenius: Medical Center University of Freiburg
Gert Zimmer: Institute of Virology and Immunology
Christopher Benner: University of California
Benjamin G. Hale: University of Zurich
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Martin Beer: Friedrich-Loeffler Institut
Martin Schwemmle: Medical Center University of Freiburg
Silke Stertz: University of Zurich

Nature, 2019, vol. 567, issue 7746, 109-112

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-0955-3

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