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

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

Nature (2019-02-23)
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, Silke Stertz
摘要

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.