Department of Pathobiological Sciences, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA.
J Virol. 2011 Dec;85(24):13195-203. doi: 10.1128/JVI.00859-11. Epub 2011 Sep 21.
The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. An Asp-to-Gly change at position 222 of the receptor-binding protein hemagglutinin (HA) correlates with more-severe infections in humans. The amino acid at position 222 of HA contributes to receptor-binding specificity with Asp (typically found in human influenza viruses) and Gly (typically found in avian and classic H1N1 swine influenza viruses), conferring binding to human- and avian-type receptors, respectively. Here, we asked whether binding to avian-type receptors enhances influenza virus pathogenicity. We tested two 2009 pandemic H1N1 viruses possessing HA-222G (isolated from severe cases) and two viruses that possessed HA-222D. In glycan arrays, viruses possessing HA-222D preferentially bound to human-type receptors, while those encoding HA-222G bound to both avian- and human-type receptors. This difference in receptor binding correlated with efficient infection of viruses possessing HA-222G, compared to those possessing HA-222D, in human lung tissue, including alveolar type II pneumocytes, which express avian-type receptors. In a nonhuman primate model, infection with one of the viruses possessing HA-222G caused lung damage more severe than did infection with a virus encoding HA-222D, although these pathological differences were not observed for the other virus pair with either HA-222G or HA-222D. These data demonstrate that the acquisition of avian-type receptor-binding specificity may result in more-efficient infection of human alveolar type II pneumocytes and thus more-severe lung damage. Collectively, these findings suggest a new mechanism by which influenza viruses may become more pathogenic in mammals, including humans.
21 世纪的首次流感大流行是由新型 H1N1 病毒引起的，这些病毒于 2009 年初出现。在血凝素（HA）受体结合蛋白的 222 位发生天冬氨酸到甘氨酸的变化与人类更严重的感染相关。HA 位置 222 的氨基酸有助于与受体结合的特异性，天冬氨酸（通常存在于人类流感病毒中）和甘氨酸（通常存在于禽源和经典 H1N1 猪流感病毒中），分别赋予与人类和禽源受体的结合能力。在这里，我们想知道是否与禽源受体的结合增强了流感病毒的致病性。我们测试了两个具有 HA-222G（从严重病例中分离得到）的 2009 年大流行 H1N1 病毒和两个具有 HA-222D 的病毒。在糖基化阵列中，具有 HA-222D 的病毒优先结合人类型受体，而具有 HA-222G 的病毒则结合禽源和人类型受体。这种受体结合的差异与具有 HA-222G 的病毒相比，与具有 HA-222D 的病毒相比，在人类肺组织中（包括表达禽源受体的肺泡 II 型上皮细胞）的有效感染相关。在非人类灵长类动物模型中，与具有 HA-222G 的病毒之一感染相比，与编码 HA-222D 的病毒感染相比，导致更严重的肺损伤，尽管对于其他具有 HA-222G 或 HA-222D 的病毒对，并未观察到这些病理差异。这些数据表明，获得禽源受体结合特异性可能导致更有效地感染人类肺泡 II 型上皮细胞，从而导致更严重的肺损伤。总的来说，这些发现表明了流感病毒在哺乳动物（包括人类）中变得更具致病性的一种新机制。
