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

Karakus, Umut; Thamamongood, Thiprampai; Ciminski, Kevin; Ran, Wei; Günther, Sira C; Pohl, Marie O; Eletto, Davide; Jeney, Csaba; Hoffmann, Donata; Reiche, Sven; Schinköthe, Jan; Ulrich, Reiner; Wiener, Julius; Hayes, Michael G B; Chang, Max W; Hunziker, Annika; Yángüez, Emilio; Aydillo, Teresa; Krammer, Florian; Oderbolz, Josua; ... (2019). MHC class II proteins mediate cross-species entry of bat influenza viruses. Nature, 567(7746), pp. 109-112. Springer Nature 10.1038/s41586-019-0955-3

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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.

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