On the pathophysiology of Enterococcus as intestinal commensal in the development of gut graft-versus-host disease

异基因造血细胞移植(allo-HCT)是治疗恶性血液病的一种重要的、根治性的免疫疗法，但它具有严重的毒性，如移植物抗宿主病(GVHD)或感染的风险。我们最近在患者和小鼠模型中证明了肠道共生肠球菌在介导allo-HCT后的这些毒性中发挥了主要作用。拟议的研究计划将重点放在宿主-微生物群-肠球菌作为病原体的相互作用网络上。这将使我们能够揭开肠球菌加重急性移植物抗宿主病的确切病理机制。我们假设并检验这是否通过刺激宿主抗原递呈细胞和树突状细胞、同种异体反应性T细胞的扩张以及肠道屏障的破坏而发生。由于所有这些因素到目前为止还没有被探索，这项拨款申请提出了一系列的体外研究和动物模型实验，以阐明这些致命的微生物-免疫相互作用。从长远来看，这项研究项目将帮助我们为几个有肠球菌感染风险的患者队列定义新的靶点来对抗肠球菌诱导的宿主毒性。

Allogeneic hematopoetic cell transplantation (allo-HCT) is an important, curative-intend immunotherapy for hematological malignancies, but it carries severe toxicities such as graft-versus-host disease (GVHD) or risk for infections. We recently demonstrated in patients and mouse models that the intestinal commensal Enterococcus plays a major role in mediating these toxicities after allo-HCT. The proposed research program will focus on the interaction network of host – microbiota – enterococci as pathogens. It will allow us to unravel the exact pathomechanisms by which Enterococcus exacerbates acute GVHD. We hypothesise and test whether this occurs either through the stimulation of host antigen-presenting and dendritic cells, the expansion of alloreactive T cells, and a disruption of intestinal barriers. As all these factors have not been explored so far, this grant application proposes a series of in vitro studies and experiments in animal models to elucidate these fatal microbe-immune interactions. In perspective, this research project will help us to define novel targets against Enterococcus-induced host toxicities for the benefit of several patient cohorts that are at risk for Enterococcus infections.