Influenza neuraminidase-specific IgG antibodies protect Fcy-receptor deficient mice against A(H1N1)pdm09 challenge

JOB EMMA; MICHAEL SCHOTSAERT; LORENA ITATÍ IBAÑEZ; ANOUK SMET; TINE YSENBAERT; FALK NIMMERJAHN; THORSTEN VOGEL; XAVIER SAELENS

Chicago

Congreso; Options IX for the control of Influenza; 2016

International Society for Influenza and Other Respiratory Virus Diseases

Influenza neuraminidase-specific IgG antibodies protect Fcy-receptor deficient mice against A(H1N1)pdm09 challengeEmma Job, Michael Schotsaert, Itati Ibanez, Anouk Smet, Tine Ysenbaert, Falk Nimmerjahn, Thorsten Vogel, Xavier SaelensVIB, Gent, East Flanders, BelgiumBackground: Interaction of antibody Fc portion and Fc receptors expressed on immune cells including dendritic cells, macrophages, neutrophils and NK cells, play a central role in the control and clearance of pathogens. In recent years, there has been a re-found awareness of the importance of these interactions in aiding the control of influenza viruses. Antibodies directed to M2e and the broadly reactive, stem hemagglutinin (HA) antibodies largely rely on interaction with Fcy receptors to mediate protection against inflenza A virus  For neuraminidase (NA), however, limited studies have examined the reliance of Fcy receptors for control.  Therefore, we evaluated if Fcy receptor-mediated mechanisms could contribute to protection by NA-specifi IgG antibodies against A(H1N1)pdm09 challenge. Method: A mouse IgG1 monoclonal antibody, named N1-C4, with NA inhibitory activity against H1N1pdm and H5N1 virus was isolated and characterized in vitro and in vivo  In addition, we generated polyclonal mouse serum comprising IgG1 and IgG2a directed against soluble recombinant A(H1N1)pdm09 NA N1-C4 and the polyclonal serum were passively transferred into wild type or Fcy receptor knock-out mice.  Morbidity, survival and lung virus loads weredetermined following challenge with A(H1N1)pdm09 of treated mice. Conclusion: Monoclonal antibody N1-C4 was able to significantly protect against weight loss in WT mice and mice genetically deficient in (i) the Fc receptor common gamma chain (gene: Fcer1g) or (ii) FcyRI (gene: Fcgr1) and FcyRIII (gene: Fcgr3) when challenged with 1 LD50 of  A(H1N1)pdm09. Polyclonal anti-NA sera was also able to protect (i) Fcer1g-/- mice, (ii) Fcgr1 and Fcgr3 double knockout mice, and (iii) Fcgr4-/- mice, which lack the activating receptor FcyRIV, from morbidity  Additionally, treatment of mice with N1-C4 could reduce viral lung loads in WT mice, however in Fcer1g-/- and Fcgr1 and Fcgr3 double knockout mice there was a trend for increased lung viral titres in comparison to WT mice  Together, our data shows that anti-NA antibodies can protect mice in the absence of activating Fcy receptors  This work indicates that direct NA inhibitory activity plays a dominant role in the control of influenza virus by antibodies directed against NA (Study funded by Sanof Pasteur)