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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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. The associated raw data for Fig. 1a are provided in Supplementary Table 1, and raw data for Fig. 1c in Supplementary Table 2. Any further relevant data are available from the corresponding authors upon reasonable request.
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We thank C. Kastenholz, K. Flämig, J. Brandel, S. Schuparis, S. Sander and G. Czerwinski for assistance; A. Dudek, P. Staeheli, D. Schnepf and A. Trkola for discussions; and R. Zengerle, D. Szabó, P. Koltay, A. Karsai and S. Zimmermann for their support. This work was supported by grants from the Swiss National Science Foundation to S.S. (310030E-164065) and B.G.H. (31003A_182464), a grant from the German Research Foundation to M.S. (SCHW 632/17-1) and M.B. (BE 5187/4-1) and the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School) to T.T. This work was also partly supported by CRIP (Center for Research on Influenza Pathogenesis) and NIAID funded Center of Excellence in Influenza Research and Surveillance (CEIRS) to A.G.-S. (HHSN272201400008C). M.W.C. and C.B. were supported by NIAID grant U19AI135972.
Nature thanks Michael Farzan, David Steinhauer and the other anonymous reviewer(s) for their contribution to the peer review of this work.