Trained Immunity Induced by mRNA-LNP

About This Grant

Trained immunity induced by mRNA-LNP Our proposal is dedicated to unraveling the intricate relationship between mRNA-LNP vaccines and innate immunity, with a particular emphasis on understanding trained immunity mechanisms and examining potential transgenerational repercussions. In the burgeoning field of mRNA-LNP vaccines, where the intersection of innate immunity and transgenerational health remains largely uncharted, our research seeks to address this critical knowledge gap. Central to our investigation is elucidating the genetic changes induced by exposure to mRNA-LNP vaccines and their heritability. Through meticulous experimentation utilizing cutting-edge molecular biology techniques, such as single-cell multiomics and spatial transcriptomics, we aim to identify genetic alterations in reproductive organs, white blood cells, and other pertinent tissues. By employing pathway analysis and cell-type-specific reporter and knock-out mouse models, we will dissect key signaling pathways and molecular mediators implicated in these genetic changes, shedding light on the mechanisms underlying mRNA-LNP-induced alterations—furthermore, our research endeavors to characterize the innate immune changes triggered by mRNA-LNP exposure. By closely mimicking the human time course scenario with multiple exposures, we aim to delineate the transition from trained immunity to innate immune tolerance, analogous to the effects observed with other stimuli like LPS. Through in vitro restimulation assays and assessments of innate immune fitness, we will probe the functional consequences of mRNA-LNP exposure on monocytes, neutrophils, and the overall innate immune system's ability to combat primary infections. Moreover, our investigation extends to examining the plasticity of trained immunity induced by mRNA-LNP and its impact on downstream adaptive immune responses. We anticipate elucidating whether the imprinted trained immunity changes are malleable or resistant to alterations and whether adjuvants play a role in shaping these responses. Additionally, we aim to elucidate how innate immune changes, particularly those affecting dendritic cells, influence adaptive immune responses to pathogens. Through a comprehensive approach involving transgenic pathogens, DC-specific antigen targeting models, adoptive cell transfer, and bone marrow chimeras, we seek to dissect the intricate interplay between innate and adaptive immunity following mRNA-LNP exposure. By addressing these multifaceted aims, our research endeavors to advance scientific understanding of mRNA- LNP vaccine immunology and its implications for transgenerational health. Through rigorous experimentation and analysis, we aim to pave the way for the development of next-generation vaccines and therapeutic interventions that harness the full potential of trained immunity for enhanced public health outcomes.