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

同种异体造血细胞移植（Allogeneic hematopoetic cell transplantation, alloo - hct）是治疗恶性血液病的重要免疫疗法，但它具有严重的毒性，如移植物抗宿主病（GVHD）或感染风险。我们最近在患者和小鼠模型中证明，肠道共生肠球菌在介导同种异体hct后的这些毒性中起主要作用。拟建的研究项目将集中于宿主-微生物群-肠球菌作为病原体的相互作用网络。这将使我们能够揭示肠球菌加剧急性GVHD的确切病理机制。我们假设并测试这种情况是否通过刺激宿主抗原呈递细胞和树突状细胞、同种异体反应性T细胞的扩增和肠道屏障的破坏发生。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。从这个角度来看，这个研究项目将帮助我们确定针对肠球菌诱导的宿主毒性的新靶点，从而使几个有肠球菌感染风险的患者群体受益。

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.