Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection

摘要 季节性流感和当前的新冠肺炎大流行造成严重的健康和经济负担。严重的病毒感染 导致急性肺损伤、炎症，并导致组织重塑和纤维化。耐人寻味的是，异类星团 在急性感染和重塑阶段，周围肺中存在基底细胞(也称为豆荚细胞)。首字母 研究表明，这些细胞能够产生I型和II型肺泡上皮细胞(AECs)。不过， 随后的谱系追踪研究表明，豆荚细胞对肺泡再生的贡献很小，如果有的话。 此外，我们的初步数据表明，豆荚细胞形成杯状细胞，导致伴随粘液化生。 通过化学感觉簇状细胞(也称为刷状细胞)的存在。值得注意的是，丛生细胞的遗传消融促进了 豆荚细胞向血管内皮细胞的分化。我们进一步的分析表明，簇状细胞表达Notch配体Jag2， 而豆荚细胞表达Notch受体，且Notch活性显著。一致地，凹槽抑制导致减少 粘液化生和促进牙槽骨再生。因此，我们假设丛状细胞促进粘液 在病毒感染时，豆荚细胞的化生和通过旁分泌JAG2/Notch激活阻碍肺泡再生。 他们设计了两个具体的目标来检验这一假设。目的：探讨丛生细胞的分子机制。 促进病毒感染后的粘液化生。AIM2：促进豆荚细胞向血管内皮细胞分化 靶向丛生细胞中的JAG2。在这个目标中，我们将结合一种新的新冠肺炎小鼠模型和豆荚细胞有机化合物 从新冠肺炎患者的肺中建立，以测试JAG/Notch诱饵在促进肺泡再生方面的效果。 总之，这一建议不仅将阐明病毒感染后损害肺再生的疾病机制，而且 还为治疗流感和冠状病毒感染的肺部提供了新的治疗方法。

ABSTRACT Seasonal influenza and the current COVID-19 pandemic cause serious health and financial burdens. Severe viral infection leads to acute lung injury, inflammation and contributes to tissue remodeling and fibrosis. Intriguingly, clusters of ectopic basal cells (also known as pod cells) are present in the peripheral lungs during acute infection and remodeling phases. Initial studies indicated that these cells were able to generate type I and II alveolar epithelial cells (AECs). Nevertheless, subsequent lineage tracing studies revealed that pod cells had minimal if any contribution to alveolar regeneration. Moreover, our preliminary data suggest that pod cells give rise to goblet cells, resulting in mucous metaplasia accompanied by the presence of chemosensory tuft cells (also known as brush cells). Significantly, genetic ablation of tuft cells promotes the differentiation of pod cells into AECs. Our further analyses revealed that tuft cells express the Notch ligand Jag2, whereas pod cells express Notch receptors with prominent Notch activation. Consistently, Notch inhibition led to reduced mucous metaplasia and improved alveolar regeneration. We therefore hypothesize that tuft cells promote mucous metaplasia of pod cells and impede alveolar regeneration via paracrine JAG2/Notch activation upon viral infection. Two specific aims were devised to test the hypothesis. Aim1: To address the molecular mechanisms by which tuft cells promote mucous metaplasia following viral infection. Aim2: To promote the differentiation of pod cells into AECs through targeting JAG2 in tuft cells. In this aim we will combine a novel COVID-19 mouse model and pod cell organoids established from COVID-19 patient lungs to test the efficacy of a JAG/Notch decoy in promoting alveolar regeneration. Together this proposal will not only elucidate the disease mechanisms impairing lung regeneration post viral infection, but also offer new therapeutic approaches to treat lungs infected by influenza and coronavirus.