The purpose of this project is to study how the Fc portion of anti-influenza antibodies regulates host immunity during virus infection. The specific activity within the Fc of IgG molecules is determined by both protein sequence and the specific saccharide components within an N-linked, complex, biantennary glycan that exists on all IgG Fes. The titer of neutralizing antibodies present in host serum is the major correlate of protection against influenza virus infection. Historically, neutralizing antibodies have been defined as those that bind the globular head of the viral hemagglutinin (HA), thereby blocking attachment to host cells. More recently, the definition has been expanded to include antibodies that bind the highly conserved stalk domain of the HA and prevent viral entry by blocking fusion with the host cell. We have recently shown that the Fc portion of influenza-specific antibodies can be a critical determinant of the concentration at which antibodies gain neutralizing activity against influenza viruses. The first two aims of this study are designed as a detailed investigation into the role of Fc-FcR engagement in broad-spectrum neutralization of influenza viruses. We will study the role and mechanisms of FcR mediated effector pathways in protection conferred through both anti-HA and anti-neuraminidase (NA) antibodies.
The final aim of our study will investigate the role of the Fc glycan in human immunity against influenza viruses. The IgG Fc glycan is a powerful regulator of antibody effector function and its specific saccharide composition can determine whether an antibody has pro- or anti-inflammatory activity in vivo. It has been observed in mice and in humans that exposure to novel immunogens results in various modifications of IgG glycans;however, little is known about how this process is regulated or the biological consequences of such modifications. Our studies, to be conducted with human samples, are designed to address three fundamental questions related to Fc glycosylation as a determinant of immunity against influenza viruses: 1) does influenza virus vaccination induce a change in glycan composition, particularly in sialylation or fucosylation of flu specific IgG Fes in humans, 2) do the route of exposure and age of the patient affect patterns of post-vaccination Fc glycosylation , and 3) how does Fc glycosylation regulate immunity against influenza viruses in in vitro and in vivo models of infection?

Public Health Relevance

Influenza viruses remain a formidable global health concern. Through the studies proposed in this project we will investigate mechanisms by which antibodies neutralize influenza viruses. These studies will inform on the design of protective antibodies for use as therapeutics and the development of novel vaccines and vaccination protocols.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109946-01
Application #
8667699
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$517,221
Indirect Cost
$88,878
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Fulton, Benjamin O; Sun, Weina; Heaton, Nicholas S et al. (2018) The Influenza B Virus Hemagglutinin Head Domain Is Less Tolerant to Transposon Mutagenesis than That of the Influenza A Virus. J Virol 92:
Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S et al. (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215:1571-1588
Coughlan, Lynda; Palese, Peter (2018) Overcoming Barriers in the Path to a Universal Influenza Virus Vaccine. Cell Host Microbe 24:18-24
Krammer, Florian; Fouchier, Ron A M; Eichelberger, Maryna C et al. (2018) NAction! How Can Neuraminidase-Based Immunity Contribute to Better Influenza Virus Vaccines? MBio 9:
Chen, Yao-Qing; Wohlbold, Teddy John; Zheng, Nai-Ying et al. (2018) Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. Cell 173:417-429.e10
Henry, Carole; Palm, Anna-Karin E; Krammer, Florian et al. (2018) From Original Antigenic Sin to the Universal Influenza Virus Vaccine. Trends Immunol 39:70-79
Broecker, Felix; Liu, Sean T H; Sun, Weina et al. (2018) Immunodominance of Antigenic Site B in the Hemagglutinin of the Current H3N2 Influenza Virus in Humans and Mice. J Virol 92:
Nachbagauer, Raffael; Shore, David; Yang, Hua et al. (2018) Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge. J Virol 92:
Pardi, Norbert; Parkhouse, Kaela; Kirkpatrick, Ericka et al. (2018) Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun 9:3361
Wang, Taia T; Bournazos, Stylianos; Ravetch, Jeffrey V (2018) Immunological responses to influenza vaccination: lessons for improving vaccine efficacy. Curr Opin Immunol 53:124-129

Showing the most recent 10 out of 80 publications