Influenza virus N-linked glycosylation and innate immunity

Abstract

Influenza viruses cause seasonal epidemics and sporadic pandemics in humans. The virus's ability to change its antigenic nature through mutation and recombination, and the difficulty in developing highly effective universal vaccines against it, make it a serious global public health challenge. Influenza virus's surface glycoproteins, hemagglutinin and neuraminidase, are all modified by the host cell's N-linked glycosylation pathways. Host innate immune responses are the first line of defense against infection, and glycosylation of these major antigens plays an important role in the generation of host innate responses toward the virus. Here, we review the principal findings in the analytical techniques used to study influenza N-linked glycosylation, the evolutionary dynamics of N-linked glycosylation in seasonal versus pandemic and zoonotic strains, its role in host innate immune responses, and the prospects for lectin-based therapies. As the efficiency of innate immune responses is a critical determinant of disease severity and adaptive immunity, the study of influenza glycobiology is of clinical as well as research interest.

Keywords: immunity; influenza; innate.

Figure 1. Influenza virus surface glycoproteins

(A) Schematic diagram of an influenza virion, showing HA and NA (provided by CDC Influenza Division/Douglas Jordan/Dan Higgins). (B) Structure of HA (top and bottom rows) and NA (middle row) showing NLG sites for early (left columns) and recent (right column) isolates of A(H3N2) and A(H1N1) IAV. ‘Oseltamivir’ (in red) indicates the NA active site. Early A(H3N2) isolate: A/Hong Kong/1/1968(H3N2). Recent A(H3N2) isolate: A/Singapore/INFIMH-16-0019/2016(H3N2). Early A(H1N1) isolate: A/South Carolina/1/1918(H1N1). Recent A(H1N1)isolate: A/Brisbane/59/2007(H1N1).

Figure 2. Evolution of influenza virus N-linked glycosylation

(A) Mean number per year of N-linked glycosylation (NLG) sites on the head and HA2 stem regions of HA, and on NA, from human isolates of A(H1N1) and A(H3N2), and B-Yamagata and B-Victoria lineages. (B) Residues of HA and NA from human A(H1N1) and A(H3N2) isolates on which more than 10% of isolates contained NLG. HA and NA sequences from human A(H1N1) and A(H3N2) isolates were downloaded from GISAID on September 6, 2018, manually curated to remove duplicates and laboratory variants, and aligned using MAFFT. Sites of potential NLG were identified based on sequence. The residue indicated as ‘23a’ in A(H3N2) represents an insert relative to earlier HA isolates that was present in some viruses isolated in the 1970s. A(H1N1) viruses did not circulate among humans between 1957 and 1976, and those years are not shown. In 2009, indicated by red dashed lines, circulating seasonal A(H1N1) viruses were replaced by a novel pandemic A(H1N1)pdm09 strain. Influenza B viruses split into B-Yamagata and B-Victoria lineages in around 1983 [180]. Influenza B isolates from before 1983 are included in the charts for both lineages, and the date of divergence is indicated with blue dashed lines.