Dynamic PB2-E627K substitution of influenza H7N9 virus indicates the in vivo genetic tuning and rapid host adaptation

Significance Deep-sequencing of viral genomes based on original specimens from H7N9-infected patients and the surrounding poultry/environment has provided the first in-depth data on virus adaptation at the interface between poultry and humans. In contrast to the consistent dominance of 627E in poultry-derived H7N9, diverse but longitudinally changing ratios of the mammalian signature substitution PB2-E627K from patient specimens indicate a dynamic viral adaptation during infection, termed “genetic tuning” of avian influenza viruses in new hosts. Furthermore, the correlation between rapid host adaptation of H7N9 PB2-627 and the disease severity in patients is brought to light. Of note, under a one-health vision, our study provides direct big data evidence that “genetic tuning” of PB2-E627K is associated with H7N9 pathogenicity during human infection. 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.