Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways

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Project Summary/Abstract: Virus infections are highly associated with the exacerbation of allergic diseases including allergic asthma, atopic dermatitis, and allergic rhinitis. IgE-mediated allergic sensitization has been shown to impair antiviral responses by innate immune cells such as monocytes- enhancing pro-inflammatory cytokine secretion, disrupting phagocytosis, and inhibiting virus-induced maturation, IFN production, and altering CD4 T cell priming. These findings suggest a role for IgE-mediated signals in modulating innate antiviral signaling pathways, however little is known regarding the molecular mechanisms behind these observations. Given the significant morbidity and economic impact of allergic diseases, a thorough understanding of IgE-mediated effects on antiviral responses is critical for the discovery of new therapeutics for viral and allergic diseases. The goal of this study is to determine how IgE-mediated allergic stimulation inhibits monocyte antiviral responses to regulate cellular functions. Using primary human monocytes, we will utilize established molecular and biochemical techniques in combination with advanced flow cytometry techniques (flow cytometry imaging and mass cytometry) and transcriptomics to: (Aim 1) determine how IgE-mediated signaling components regulate early antiviral recognition pathways, (Aim 2) determine the mechanisms by which IgE-induced IL-10 regulates interferon receptor signaling, and (Aim 3) translate the in vitro findings by comparing monocyte antiviral responses in individuals with high and low serum IgE. These studies will fill a large gap in our current knowledge of how IgE-mediated processes modulate antiviral responses to promote virus-induced allergic exacerbations. Dr. Regina K. Rowe, M.D. Ph.D. is currently an Assistant Professor of Pediatric Infectious Diseases at the University of Rochester Medical Center. She received her Ph.D. from Washington University in St. Louis in Molecular Microbiology and Microbial Pathogenesis where she investigated the interactions of hantaviruses with the respiratory epithelium. She then received medical training at St. Louis University followed by Pediatric Residency and Infectious Disease Fellowship training at UT Southwestern where her postdoctoral research focused on the effects of allergic stimulation on monocyte-induced T cell priming. This career development award will expand her expertise in systems immunology through training in cell signaling mechanisms, advanced flow cytometry methods, and bioinformatics. As a pediatric physician-scientist, she will utilize her skills as an infectious disease specialist trained in both human immunology and virology to establish a scientific platform to answer a breadth of questions involving host-pathogen interactions in the context of human disease. Her innovative approaches have the potential to identify new therapeutics to treat virus-induced allergic diseases, and ultimately prevent disease development, exacerbation, and progression.