Synthetically rewired macrophages to foster tissue regeneration post virus induced lung damage

有针对性地支持身体自身的功能代表了一种新的、有吸引力的对抗疾病的策略（称为：宿主导向疗法，HDT）。HDT的一个焦点是减少恶化的炎症并平衡病理部位的免疫反应性。在其他疾病中，肺部的细菌和病毒感染与严重的组织损伤相关，导致感染相关的致死性并促进微生物生态位。为了支持组织再生，使用巨噬细胞的基于细胞的免疫疗法是特别感兴趣的，因为这些细胞（i）固有地提供组织再生和稳态的功能，（ii）迁移到受损组织和（iii）感测组织环境的信号，并且可以诱导促炎或抗炎反应。在这个创新项目中，我们的目标是开发一种基于巨噬细胞的HDT策略，该策略可以干扰病原体诱导的过度炎症并减少恶化的组织损伤。使用合成生物学，将开发基因修饰的传感器/效应器巨噬细胞，其自主地将内源性感染相关信号转化为最终导致组织再生的可靠反应。将在免疫活性小鼠肺部感染的背景下对小鼠传感器/效应器巨噬细胞以及在先进的体外系统以及人源化小鼠中对人传感器/效应器巨噬细胞评价该策略。

The targeted support of the body's own functions represents a new, attractive strategy for combating disease (referred to as: host-directed therapy, HDT). One focus of HDT is to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology. Among other diseases, bacterial and viral infections of the lung are associated with severe tissue damage, contributing to infection associated lethality and promoting microbial niches. To support tissue regeneration, cell-based immunotherapies with macrophages are of particular interest, as these cells (i) intrinsically provide functions for tissue regeneration and homeostasis, (ii) migrate to damaged tissue and (iii) sense the signals of the tissue environment and can induce pro- or anti-inflammatory responses. In this innovative project we aim to develop a macrophage based HDT strategy that perturbs pathogen-induced hyper-inflammation and reduces exacerbated tissue damage. Using synthetic biology, genetically modified sensor/effector macrophages will be developed that autonomously convert endogenous, infection-associated signals into reliable responses that ultimately lead to tissue regeneration. This strategy will be evaluated for mouse sensor/effector macrophages in the context of pulmonary infection in immunocompetent mice and for human sensor/effector macrophages in advanced in vitro systems as well as in humanized mice.