Understanding the Role of Immunoglobulin A in Respiratory Virus Infection

Effective immunity against respiratory viruses is facilitated by mucosal immunity, which relies, in part, on the action of immunoglobulin A (IgA). Little is known about the mechanisms through which IgA mediates protection against respiratory virus infection. Indeed, the effect of subclasses (IgA1 and IgA2), relative contributions of neutralization vs. Fc-mediated effector functions, and antibody structures (monomeric, dimeric, secretory) on protection against SARS-CoV-2 and influenza A virus (IAV) infections has so far been elusive. The overarching aim of this research is to systematically define how the aforementioned features of IgA impact its ability to protect against IAV and SARS-CoV-2 infection. We hypothesize that the interaction between IgA and the Fc alpha receptor plays a vital role in the maintenance of immunity against these respiratory viruses. The first aim of research is to characterize how IgA subclass (IgA1 vs. IgA2) affects binding and neutralization properties. A variety of anti-hemagglutinin (HA) monoclonal antibodies against IAV, and anti-S protein monoclonal antibodies against SARS-CoV-2 will be cloned, expressed, and purified. Each will be produced in monomeric, dimeric, and secretory forms, and binding kinetics will be measured by ELISA and biolayer interferometry assays. Neutralization assays will also be performed using live viruses. The second aim of research is to determine the impact of IgA subclass and structure on the ability to activate neutrophils via the Fc alpha receptor. Virus-IgA complexes will be incubated with neutrophils to measure their activation. Finally, the third aim of research is to determine how IgA subclass and structure influence efficacy in vivo using transgenic mice expressing the human Fc alpha receptor.