Single-cell transcriptome reveals a role for neutrophil elastase in immune homeostasis and shaping of host early responses to vaccines 4334

Abstract Description Induction of mucosal immunity is generally believed to require stimulation of mucosal inductive sites through vaccines administered via a mucosal route. We recently reported that supplementation with a neutrophil elastase inhibitor improves the immunogenicity of alum-based injected vaccines. Importantly, inhibition of neutrophil elastase (NE) triggers innate signals that promote the induction of mucosal immunity and secretory IgA responses; however, the underlying mechanisms remain incompletely understood. Single-cell RNA sequencing analysis of wild-type and NE-deficient mice revealed that NE regulates the transcriptional profile of myeloid cells at steady state conditions. Moreover, genes differentially regulated in lymphoid tissues after vaccination in NE-deficient mice or in wild-type mice with NE inhibition suggest lower expression of inflammatory cues and altered iron metabolism. Finally, we observed that pretreatment of mice with an NE inhibitor (NEI) ahead of vaccination accelerated the kinetics of vaccine-specific responses and broadened the profile of antibody and T cell immunity. Taken together, our findings suggest that NE plays a critical role in shaping early vaccine response, and thus, represents a promising molecular target for improving the kinetics and breadth of immune responses to mucosal and injected vaccines. Funding Sources NIH R01AI145144 Topic Categories Vaccines and Immunotherapy (VAC)