Shenzhen Key Laboratory of Pathogen and Immunity, State Key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, 518112 Shenzhen, China.
NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, 102206 Beijing, China.
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23807-23814. doi: 10.1073/pnas.2013267117. Epub 2020 Sep 1.
Avian-origin influenza viruses overcome the bottleneck of the interspecies barrier and infect humans through the evolution of variants toward more efficient replication in mammals. The dynamic adaptation of the genetic substitutions and the correlation with the virulence of avian-origin influenza virus in patients remain largely elusive. Here, based on the one-health approach, we retrieved the original virus-positive samples from patients with H7N9 and their surrounding poultry/environment. The specimens were directly deep sequenced, and the subsequent big data were integrated with the clinical manifestations. Unlike poultry/environment-derived samples with the consistent dominance of avian signature 627E of H7N9 polymerase basic protein 2 (PB2), patient specimens had diverse ratios of mammalian signature 627K, indicating the rapid dynamics of H7N9 adaptation in patients during the infection process. In contrast, both human- and poultry/environment-related viruses had constant dominance of avian signature PB2-701D. The intrahost dynamic adaptation was confirmed by the gradual replacement of 627E by 627K in H7N9 in the longitudinally collected specimens from one patient. These results suggest that host adaptation for better virus replication to new hosts, termed "genetic tuning," actually occurred in H7N9-infected patients in vivo. Notably, our findings also demonstrate the correlation between rapid host adaptation of H7N9 PB2-E627K and the fatal outcome and disease severity in humans. The feature of H7N9 genetic tuning in vivo and its correlation with the disease severity emphasize the importance of testing for the evolution of this avian-origin virus during the course of infection.
禽流感病毒通过变体在哺乳动物中更有效地复制的进化，克服了种间障碍的瓶颈并感染人类。病毒在患者中的遗传替换的动态适应及其与禽流感病毒毒力的相关性在很大程度上仍未被揭示。在这里，我们基于“同一健康”方法，从 H7N9 患者及其周围的家禽/环境中检索到原始的病毒阳性样本。对标本进行直接深度测序，随后将大数据与临床表现进行整合。与禽源性/环境源性样本中一致占主导地位的 H7N9 聚合酶碱性蛋白 2（PB2）的 627E 不同，患者样本中具有哺乳动物特征 627K 的多样化比例，表明在感染过程中 H7N9 在患者中快速适应。相比之下，人和家禽/环境相关的病毒都具有恒定的 PB2-701D 主导的禽源特征。通过对一名患者的纵向采集标本中 H7N9 中 627E 逐渐被 627K 取代，证实了宿主内的动态适应。这些结果表明，宿主为更好地适应新宿主而进行的病毒复制，称为“遗传调整”，实际上发生在 H7N9 感染患者体内。值得注意的是，我们的研究结果还表明，H7N9 PB2-E627K 的快速宿主适应与人类的致命结局和疾病严重程度之间存在相关性。H7N9 在体内的遗传调整特征及其与疾病严重程度的相关性强调了在感染过程中检测这种禽流感病毒进化的重要性。
