Influenza A viruses (IAV) pose substantial burden on human and animal health. Avian, swine and human IAV bind sialic acid on host glycans as receptor, whereas some bat IAV require MHC class II complexes for cell entry. It is unknown how this difference evolved and whether dual receptor specificity is possible. Here we show that human H2N2 IAV and related avian H2N2 possess dual receptor specificity in cell lines and primary human airway cultures. Using sialylation-deficient cells, we reveal that entry via MHC class II is independent of sialic acid. We find that MHC class II from humans, pigs, ducks, swans and chickens but not bats can mediate H2 IAV entry and that this is conserved in Eurasian avian H2. Our results demonstrate that IAV can possess dual receptor specificity for sialic acid and MHC class II, and suggest a role for MHC class II-dependent entry in zoonotic IAV infections.

甲型流感病毒 （IAV） 对人类和动物健康构成沉重负担。禽、猪和人 IAV 作为受体在宿主聚糖上结合唾液酸，而一些蝙蝠 IAV 需要 MHC II 类复合物才能进入细胞。目前尚不清楚这种差异是如何演变的，以及双受体特异性是否可能。在这里，我们表明人 H2N2 IAV 和相关禽 H2N2 在细胞系和原代人气道培养物中具有双重受体特异性。使用唾液酸化缺陷细胞，我们揭示了通过 MHC II 类进入与唾液酸无关。我们发现来自人类、猪、鸭、天鹅和鸡而不是蝙蝠的 MHC II 类可以介导 H2 IAV 的进入，这在欧亚禽 H2 中是保守的。我们的结果表明，IAV 可以具有唾液酸和 MHC II 类的双重受体特异性，并表明 MHC II 类依赖性进入在人畜共患 IAV 感染中的作用。