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

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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.