Unveiling the hidden regulators: deciphering endogenous retroelement control of allergic Type 2 immune response

George Washington University, Washington DC

Investigators

Abstract

SUMMARY The global burden of pulmonary allergic diseases, including asthma, continues to rise, with an estimated 262 million cases worldwide. House dust mites (HDM) are among the most common aeroallergens, sensitizing 85% of asthma patients. The pathogenesis of pulmonary allergic diseases is multifaceted, involving genetic, epigenetic, environmental, and host factors. While the components and functions of Type 2 immune mediators driving allergic responses are well understood, the early immunological triggers that initiate Type 2 immunity at mucosal barrier surfaces remain unclear. Given that 10% of the mammalian genome consists of endogenous retroviruses (ERVs) and that their reactivation has been linked to the progression of several diseases, though not yet studied in the context of allergies, this pioneering study will investigate the role of ERVs in the early development of Type 2-dominated inflammation in the lungs induced by HDM. We hypothesize that the reactivation of ERVs during allergen sensitization fine-tunes Type 2 immune responses in the mucosal epithelium, affecting Th2 cells, eosinophils, mucus production, and IgE levels, ultimately exacerbating allergic phenotypes. Building on preliminary data showing upregulation of ERVs in both human and mouse allergic tissues, as well as in lung epithelial cell lines stimulated with HDM allergens, this research will explore the downstream effects of Type 2 allergic inflammation triggered by HDM-induced ERV reactivation (Aim 1) and investigate the upstream regulatory epigenetic pathways that modulate ERV expression during allergic inflammation (Aim 2). Using in vitro and in vivo conditional knockout mouse models and employing advanced techniques such as multiparameter flow cytometry, high-throughput cytokine and chemokine profiling, bulk and single-cell RNA sequencing, and ATAC-seq in allergic tissues and human and mouse epithelial cell lines stimulated with HDM, this study will provide insights into when, where, and how ERVs regulate downstream Type 2-associated allergic responses following HDM sensitization. Key components of the research include mapping ERV reactivation in the allergic airway mucosa, analyzing the temporal dynamics of ERV reactivation during the development of Type 2 inflammation, assessing the effects of ERV depletion (using mutant mice) or blockade (with antiretroviral drugs) on Type 2 inflammatory responses in the lungs, and investigating the epigenomic regulation of ERV-induced Th2 responses. By unraveling the intricate network involving the endogenous virome, the mucosal barrier, and HDM-driven pulmonary Type 2 immunity, we will take allergy research in a new direction. We will explore the previously unexamined role of endogenous retroelements in regulating Type 2 immune responses in both mouse and human models, which may ultimately pave the way for new therapeutic strategies against asthma and related conditions.