Role of ACE2 in Maternal SARS-CoV-2 Infection Predisposed Susceptibility to Inflammatory Lung Disease in Offspring

Project title: Role of ACE2 in Maternal SARS-CoV-2 Infection Predisposed Susceptibility to Inflammatory Lung Disease in Offspring. The COVID-19 pandemic's aftermath carries potential long-term health risks, especially for offspring exposed to maternal SARS-CoV-2 (SCV2) infections. This project ventures into uncharted territories, examining these long- lasting impacts with a specific focus on the pulmonary system. At the heart of our investigation is the humanized ACE2 mouse model, designed in-house, to authentically replicate human susceptibility to SCV2. ACE2 plays a pivotal dual role in COVID-19 disease: as the primary receptor for SCV2 and as a vital modulator of inflammatory responses. Our preliminary studies suggest maternal SCV2 infections during pregnancy may adversely modulate fetal ACE2 levels, which could result in heightened inflammatory reactions in the lungs of the offspring, potentially predisposing them to respiratory complications throughout their lives. Our research intends to: 1. Delve deep into the enduring effects of maternal SCV2 infections on the offspring's pulmonary inflammatory response, determining the potential transgenerational transmission of these predispositions. 2. Decode the mechanisms by which IL-6 impacts fetal ACE2 in the backdrop of maternal SCV2 infections, translating our findings from human cohorts and mouse models into actionable insights. 3. Scrutinize the intricate interplay of ACE2 and SDF-1 in bone marrow during prenatal development, and its subsequent effect on an offspring's inflammatory response, especially in the pulmonary system. This multi-faceted investigation aims not only to fill existing knowledge gaps but to shape the future of preventative and therapeutic interventions, ensuring healthier outcomes for subsequent generations impacted by this pandemic.