Genomic Signatures for Avian H7N9 Viruses Adapting to Humans

Abstract

An avian influenza A H7N9 virus emerged in March 2013 and caused a remarkable number of human fatalities. Genome variability in these viruses may provide insights into host adaptability. We scanned over 140 genomes of the H7N9 viruses isolated from humans and identified 104 positions that exhibited seven or more amino acid substitutions. Approximately half of these substitutions were identified in the influenza ribonucleoprotein (RNP) complex. Although PB2 627K of the avian virus promotes replication in humans, 45 of the 147 investigated PB2 sequences retained the E signature at this position, which is an avian characteristic. We discovered 10 PB2 substitutions that covaried with K627E. An RNP activity assay showed that Q591K, D701N, and M535L restored the polymerase activity in human cells when 627K transformed to an avian-like E. Genomic analysis of the human-isolated avian influenza virus is crucial in assessing genome variability, because relationships between position-specific variations can be observed and explored. In this study, we observed alternative positions that can potentially compensate for PB2 627K, a well-known marker for cross-species infection. An RNP assay suggested Q591K, D701N, and M535L as potential markers for an H7N9 virus capable of infecting humans.

A pilot study on primary cultures of human respiratory tract epithelial cells to predict patients’ responses to H7N9 infection

“…One of the main findings of this study was that the H7N9 virus showed equivalent and efficient replication in epithelial cells derived from both the upper and lower anatomical locations. This finding indicates that avian influenza A(H7N9) virus A/Taiwan/4/2014 [28], similar to avian influenza A(H7N9) virus A/Anhui/1/13 [9], can bind to both α2, 6-linked and α2, 3-linked sialic acids of the upper and lower respiratory tract epithelial cells. Intriguingly, infections of the upper airways were associated with a marked release of IL-8, IFN-γ, and TNF-α within 72 h p.i.…”

“…We used influenza A/Taiwan/4-CGMH/2014 (TW4/ H7N9) [28] and A/California/07/2009 (H1N1pdm) [27] in this study. All of the H7N9 infection-related procedures were conducted in biosafety level 3 facilities.…”

“…All of the H7N9 infection-related procedures were conducted in biosafety level 3 facilities. A/Taiwan/4-CGMH/2014 is genetically close to the A/Anhui/1/2013 strain [28]. The viral RNA quantities were determined by a plaque assay on Madin-Darby canine kidney epithelial cells.…”

“…In the present study, we addressed the hypothesis that respiratory epithelial cells from different human donors would vary in their response to influenza virus infections. To determine the impact of age on cellular response after influenza virus infection, commercial NHBE cells cultured from 24-year-old and 69-year-old donors were infected with both H1N1pdm virus (A/California/07/2009 [27]) and avian H7N9 virus (A/Taiwan/4-CGMH/2014 [28]), and viral growth kinetics and the cytokine response were compared. We further explored how different donors' characteristics (i.e., age, sex, medical comorbidities, and obesity) could influence both virus replication kinetics and the cytokine response to experimental H7N9 infections.…”

Research progress on human infection with avian influenza H7N9

“…Monitoring the change of this site is of great significance for vaccine development and upgrading [59]. Change of antigenicity R148K [58] Change of antigenicity L217Q [59] Increases affinity for sialic acid α2-6 receptor Q226L/I [49,[51][52][53][54][55][56][57] Increases affinity for sialic acid α2-6 receptor G186V [51][52][53][54][55]57] Increases affinity for sialic acid α2-6 receptor G228S [50] Cleavage peptides PEVPKRKRTAR↓G [6,7] NA b Reduces drug sensitivity R292K [54,60,61] Reduces drug sensitivity H274Y [61] Reduces drug sensitivity E119V [62] Reduces drug sensitivity I222K [63] PB2 Enhances viral transcription and replication in cells K526R [61] Enhances viral transcription and replication in cells E627K [51,64,65] Increases virulence in mammalian models D701N [51,64,65] Restores polymerase activity M535L [66][67][68] Host signature amino acids (avian to human) T271A [69] Increases viral replication and virulence Q591K [66][67][68] Increases viral replication and virulence A588V [8] Host signature amino acids (avian to human) K702R …”