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 GND; Reiche, Sven GND; Schinköthe, Jan GND; Ulrich, Reiner Georg GND; Wiener, Julius; Hayes, Michael G. B.; Chang, Max W.; Hunziker, Annika; Yángüez, Emilio; Aydillo, Teresa; Krammer, Florian; Oderbolz, Josua; Meier, Matthias; Oxenius, Annette; Halenius, Anne; Zimmer, Gert; Benner, Christopher; Hale, Benjamin G.; García-Sastre, Adolfo; Beer, Martin GND; Schwemmle, Martin; Stertz, Silke

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.




Karakus, Umut / Thamamongood, Thiprampai / Ciminski, Kevin / et al: MHC class II proteins mediate cross-species entry of bat influenza viruses. 2019.


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