Placental Responses to Maternal Viral Infection Drive Sex-Dimorphic Offspring Immune Reprogramming

About This Grant

PROPOSAL ABSTRACT Maternal infections during pregnancy have been demonstrated to significantly influence offspring health by altering fetal immune development and increasing disease susceptibility in neonates. However, the long-term effects of maternal viral infection on offspring immunity and the underlying mechanisms remain unclear. Our long-term goal is to uncover these underlying mechanisms to develop preventive and therapeutic strategies, ultimately improving offspring immunity against infections. The overall objective of this application is to determine how maternal infection during pregnancy reshapes long-term offspring antibacterial immunity through hematopoietic stem cell (HSC) reprogramming mediated by placenta inflammasome signaling, increasing offspring susceptibility to infections after birth. The central hypothesis to be tested is that maternal viral infection induces differential placental inflammasome response, reprogramming offspring HSC and increasing their susceptibility to infections postnatally in a sex-specific manner. The rationale for this project is that maternal viral infection significantly impairs offspring neutrophil function and result in hypersensitivity to LPS specifically in male offspring and sex-specific placental inflammasome IL-1 signaling may underlie this compromised offspring immunity. The central hypothesis will be tested by pursuing three specific aims: 1) Determine how maternal viral infection alters offspring immunity via HSC reprogramming; we will evaluate the fetal and offspring HSC fate trajectories and function potential, as well as transcriptional and epigenetic signatures of offspring HSC. 2) Identify placenta signaling pathways driving sex-specific offspring HSC reprogramming; we will determine if IL- 1 is necessary mediating offspring HSC immune reprogramming, and the origins of IL-1 in response to viral exposure. 3) Determine the sex-specific placental inflammasome activity in human pregnancy and its impact on human fetal HSC reprogramming; we will characterize the sex-dimorphic and gestation-dependent trophoblast inflammasome activation in human placentas and establish a placenta-fetal interface chip to study the impact of inflammasome signaling on the differentiation of human immune progenitor cells. The proposed study is significant because it is expected to offer new mechanistic insights into the impact of maternal viral infection on postnatal long-term offspring immunity. By identifying molecular and cellular mechanisms linking maternal viral infection to sex-dimorphic immune reprogramming, we will provide groundbreaking insights into sex differences in susceptibility to infections, vaccine responses, and allergies associated with maternal viral exposures. The findings may lead to biomarkers for early detection of at-risk children and inform precision medicine strategies, including sex-dimorphic interventions to mitigate adverse immune outcomes in future generations.