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Abstract
Influenza A virions are highly pleomorphic, exhibiting either spherical or filamentous morphology. The influenza A virus strain A/Udorn/72 (H3N2) produces copious amounts of long filaments on the surface of infected cells where matrix protein 1 (M1) and 2 (M2) play a key role in virus filament formation. Previously, it was shown that an anti-M2 ectodomain (M2e) antibody could inhibit A/Udorn/72 virus filament formation. However, the study of these structures is limited by their small size and complex structure. Here, we show that M2e-specific IgG1 and IgG2a mouse monoclonal antibodies can reduce influenza A/Udorn/72 virus plaque growth and infectivity in vitro. Using Immuno-staining combined with super-resolution microscopy that allows us to study structures beyond the diffraction limit, we report that M2 is localized at the base of viral filaments that emerge from the membrane of infected cells. Filament formation was inhibited by treatment of A/Udorn/72 infected cells with M2e-specific IgG2a and IgG1 monoclonal antibodies and resulted in fragmentation of pre-existing filaments. We conclude that M2e-specific IgGs can reduce filamentous influenza A virus replication in vitro and suggest that in vitro inhibition of A/Udorn/72 virus replication by M2e-specific antibodies correlates with the inhibition of filament formation on the surface of infected cells.
Highlights
Influenza A viruses are enveloped with a negative-sense RNA genome consisting of eight ribonucleoprotein segments
We demonstrate that the matrix protein 2 (M2) ectodomain (M2e)-specific IgG monoclonal antibody (MAb) 37 (IgG1) and 65 (IgG2a), both directed against a similar part of M2e, and MAb 148 (IgG1, directed against Ser2-Thr9) can reduce the plaque growth of A/Udorn/72 virus (Table 1, Fig. 1a)
The plaque size of Udorn was significantly smaller in the presence of all three M2e-specifc MAbs used at a concentration of 100 μg/mL compared to isotype control antibody (Fig. 1a,b)
Summary
Influenza A viruses are enveloped with a negative-sense RNA genome consisting of eight ribonucleoprotein segments. Influenza virus budding results in the formation of filamentous, bacilliform or spherical particles, depending on the virus strains that are used. Some influenza A virus strains, are susceptible to a direct in vitro antiviral effect of M2e-specific IgGs24 In this case, M2e-specific IgGs perturb critical interactions between the M1 and M2 proteins, which in turn affect the interaction of M1 with the viral ribonucleoprotein complexes. Virions assembly is compromised[25] Evidence for such an effect on the interaction between M1 and M2 is based on the observation that treatment of influenza A virus-infected cells with the M2e-specific monoclonal antibody (MAb) 14C2 results in a loss of filament formation and reduces infectivity of some influenza A virus strains such as A/Udorn/72 in vitro[8,25]. The notion that influenza HA associates with lipid-raft domains has been challenged recently[6,31]
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