Abstract
Influenza A hemagglutinin (HA) is a homotrimeric glycoprotein composed of a fibrous globular stem supporting a globular head containing three sialic acid binding sites responsible for infection. The H7N9 strain has consistently infected an avian host, however, the novel 2013 strain is now capable of infecting a human host which would imply that the HA in both strains structurally differ. A better understanding of the structural differences between the avian and human H7N9 strains may shed light into viral evolution and transmissibility. In this study, we elucidated the structural differences between the avian and human H7N9 strains. Throughout the study, we generated HA homology models, verified the quality of each model, superimposed HA homology models to determine structural differences, and, likewise, elucidated the probable cause for these structural differences. We detected two different types of structural differences between the novel H7N9 human and representative avian strains, wherein, one type (Pattern-1) showed three non-overlapping regions while the other type (Pattern-2) showed only one non-overlapping region. In addition, we found that superimposed HA homology models exhibiting Pattern-1 contain three non-overlapping regions designated as: Region-1 (S1571-A1601); Region-3 (R2621-S2651); and Region-4 (S2701-D2811), whereas, superimposed HA homology models showing Pattern-2 only contain one non-overlapping region designated as Region-2 (S1371-S1451). We attributed the two patterns we observed to either the presence of salt bridges involving the E1141 residue or absence of the R1411:D771 salt bridge. Interestingly, comparison between the human H7N7 and H7N9 HA homology models showed high structural similarity. We propose that the putative absence of the R1411:D771 salt bridge coupled with the putative presence of the E1141:R2621 and E1141:K2641 salt bridges found in the 2013 H7N9 HA homology model is associated to human-type receptor binding. This highlights the possible significance of HA salt bridge formation modifications in viral infectivity, immune escape, transmissibility and evolution.
Highlights
Influenza A virus is an RNA virus that initiates infection primarily attributed to the hemagglutinin (HA) glycoprotein
To elucidate the structural differences observed in Pattern-1, we looked into the neighboring strands of each non-overlapping region (Region-1, -2, and -3), identified amino acid residue/s and its structural properties that vary between the superimposed HA homology models, and, subsequently, determine its putative effects on the non-overlapping region/s
Throughout this study we identified two patterns of structural differences observed in the superimposed HA homology models of the novel H7N9 human and representative avian strains
Summary
Influenza A virus is an RNA virus that initiates infection primarily attributed to the hemagglutinin (HA) glycoprotein. HA is a homotrimeric glycoprotein comprising of a fibrous globular stem inserted into the viral membrane supporting a globular head containing three sialic acid binding sites [1,2,3]. HA receptor-binding avidity has been correlated to HA antigenic drift [10] which is hypothesized to, subsequently, influence neuraminidase antigenic drift [11]. This highlights the importance of the HA receptor-binding in viral infectivity, immune escape, transmissibility and evolution [6,8,10,12]
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