Abstract
IgA antibodies, which are secreted onto the mucosal surface as secretory IgA antibodies (SIgAs), play an important role in preventing influenza virus infection. A recent study reported that anti-hemagglutinin (HA) head-targeting antibodies increase anti-viral functions such as hemagglutination inhibition (HI) and virus neutralization (NT), in addition to HA binding activity (reactivity) via IgA polymerization. However, the functional properties of anti-viral IgA antibodies with mechanisms of action distinct from those of anti-HA head-targeting antibodies remain elusive. Here, we characterized the functional properties of IgG, monomeric IgA, and polymeric IgA anti-HA stalk-binding clones F11 and FI6, and B12 (a low affinity anti-HA stalk clone), as well as Fab-deficient (ΔFab) IgA antibodies. We found that IgA polymerization impacts the functional properties of anti-HA stalk antibodies. Unlike anti-HA head antibodies, the anti-viral functions of anti-HA stalk antibodies were not simply enhanced by IgA polymerization. The data suggest that two modes of binding (Fab paratope-mediated binding to the HA stalk, and IgA Fc glycan-mediated binding to the HA receptor binding site (RBS)) occur during interaction between anti-stalk HA IgA antibodies and HA. In situations where Fab paratope-mediated binding to the HA stalk exceeded IgA Fc glycan-mediated binding to HA RBS, IgA polymerization increased anti-viral functions. By contrast, when IgA Fc glycan-mediated binding to the HA RBS was dominant, anti-viral activity will fall upon IgA polymerization. In summary, the results suggest that coordination between these two independent binding modules determines whether IgA polymerization has a negative or positive effect on the anti-viral functions of anti-HA stalk IgA antibodies.
Highlights
Influenza is a highly contagious infectious disease caused by the influenza virus
IgA polymers were produced using methods established previously [11], and successful production of IgA polymers of antibody clones F11 and FI6 was confirmed by SDS-PAGE (S3D Fig), HPLC (S3B Fig), and sedimentation velocity analytical ultracentrifugation (SV-area under the reactivity curve (AUC); S3E–S3I Fig) analyses
Anti-HA stalk IgG antibodies bind to the HA stalk region via Fab paratopes in the absence of Fc glycan-mediated binding to the HA receptor binding site (RBS); they neutralize viruses by inhibiting viral egress through “NA steric hindrance”, resulting in NI activity (Fig 5A)
Summary
Influenza is a highly contagious infectious disease caused by the influenza virus. IgA antibodies, which are secreted onto the mucosal surface as secretory IgA antibodies (SIgAs), play an important role in preventing influenza virus infection [1,2,3]. Available influenza vaccines are of the injectable type, which induce systemic IgG responses but not mucosal IgA responses; such vaccines mitigate the severity of disease following virus infection but cannot prevent infection in the first place [4]. Intranasally-administered inactivated vaccines, which are currently under development, induce secretion of SIgAs by respiratory mucosal tissues [5,6]. Intranasal inactivated influenza vaccines are promising vaccine candidates that could protect humans from infection by influenza virus [7,8]
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