Regulation Of Lung Immunity By Antibody Glycosylation

The glycans present on IgG antibodies are key determinants of immune complex (IC) signaling by FcγRs, with modulations in IgG glycosylation triggering distinct antibody effector functions in response to infection or immunization. While FcγR signaling pathways are broadly characterized, with established functions in cell maturation, phagocytosis, production or release of soluble factors, and suppression or modulation of activating signals, little is known about how these responses are integrated at the tissue level. Of particular interest is understanding how IgG glycoforms regulate antibody-mediated functions in the lung, the immune interface for respiratory pathogens and a tissue with unique cellular features, including lung-specific, FcγR-expressing cells. Using a newly developed system in mice that express human FcγRs, we have found that IC glycosylation, specifically fucosylation and sialylation, can regulate lung inflammatory responses. We now propose to examine the role of distinct IgG IC glycoforms in regulating the outcomes of SARS-CoV-2 and IAV virus infections, as we have observed that different patterns of IC glycosylation correlate with disease risk in these two infections. We will study how signaling by differentially glycoslylated IC impacts viral and host immune readouts in SARS-CoV- 2 and IAV virus infections, and we will define molecular mechanisms governing the regulation of lung inflammation by IC. Our hope is that these studies will reveal aspects of how the host IgG glycome contributes to heterogeneous outcomes of infection with SARS-CoV-2 and IAV viruses and reveal mechanisms that can be targeted to prevent the severe lung inflammation that leads to ARDS and mortality in these and potentially other respiratory infections.