Glycosylation of Hemagglutinin and Neuraminidase of Influenza A Virus as Signature for Ecological Spillover and Adaptation among Influenza Reservoirs

Paul Kim,Soon Kwon,Yo Jang,Baik Seong,Chung Lee,Gyoonhee Han

doi:10.3390/v10040183

Abstract

Glycosylation of the hemagglutinin (HA) and neuraminidase (NA) of the influenza provides crucial means for immune evasion and viral fitness in a host population. However, the time-dependent dynamics of each glycosylation sites have not been addressed. We monitored the potential N-linked glycosylation (NLG) sites of over 10,000 HA and NA of H1N1 subtype isolated from human, avian, and swine species over the past century. The results show a shift in glycosylation sites as a hallmark of 1918 and 2009 pandemics, and also for the 1976 “abortive pandemic”. Co-segregation of particular glycosylation sites was identified as a characteristic of zoonotic transmission from animal reservoirs, and interestingly, of “reverse zoonosis” of human viruses into swine populations as well. After the 2009 pandemic, recent isolates accrued glycosylation at canonical sites in HA, reflecting gradual seasonal adaptation, and a novel glycosylation in NA as an independent signature for adaptation among humans. Structural predictions indicated a remarkably pleiotropic influence of glycans on multiple HA epitopes for immune evasion, without sacrificing the receptor binding of HA or the activity of NA. The results provided the rationale for establishing the ecological niche of influenza viruses among the reservoir and could be implemented for influenza surveillance and improving pandemic preparedness.

Highlights

Influenza viruses have taken a heavy toll on public health through annual epidemics and occasional pandemics
We confirmed that the emergence of H1N1 pandemics coincided with the sudden disappearance of particular glycosylation sites [11], our analyses newly found that the H1N1 swine influenza (A/New Jersey/76 H1N1) had a glycosylation pattern remarkably similar to the 1918 and 2009 H1N1 pandemic strains
Potential N-linked glycosylation (NLG) sites in the complete sequences of HA and NA proteins of influenza viruses isolated from avian, human, or swine species during the period 1918–2017 were predicted using NetNglyc 1.0 (Kemitorvet, Denmark)

Summary

Introduction

Influenza viruses have taken a heavy toll on public health through annual epidemics and occasional pandemics. A new strain of influenza virus is transmitted to humans from an animal reservoirs, and can give rise to an influenza pandemic with considerably higher morbidity and mortality than seasonal epidemics [2]. Influenza A virus has an eight-segmented RNA genome and high levels of variability in viral strains due to a high propensity for genetic mutations. Viruses 2018, 10, 183 surface proteins, hemagglutinin (HA) and neuraminidase (NA) undergo continuous genetic changes, which enables the virus to escape host immune responses [3]. The HA proteins undergo post-translational modifications by adding oligosaccharides to the consensus N-X-S/T (where X is any amino acid except proline) glycosylation motif [4]. Glycosylation in HA is important for the folding and stability of the protein [5,6], and, in some cases, significantly affects receptor binding and cleavage of the precursor HA0 protein, influencing the virulence and antigenicity of the virus [7]

Methods

Results

Conclusion