The role of CEACAM-recognition for mucosal colonization by bacterial pathogens

粘膜表面的定殖是几种微生物致病的关键步骤。当病原体通过特异性粘附素接触上皮表面时，受感染的细胞可以通过从下面的组织分离来响应细菌的挑战，该过程被称为剥离。细菌如何克服粘膜上皮的剥脱反应尚不清楚。我们先前已经观察到，人上皮细胞与几种病原菌的接触导致感染的真核细胞的整合素活性和底物结合增强，从而防止它们在体外从细胞外基质脱离。这种宿主反应取决于真核细胞上人CEA相关细胞粘附分子（CEACAMs）的存在以及细菌一侧的CEACAMs结合粘附素，并需要CEACAMs启动的CD 105从头表达。在这项研究中，我们将剖析的分子机制，连接CD105的表达调节整合素的活动。此外，我们将应用一个新建立的人源化小鼠模型，以评估在面对细菌CEACAM参与，CD105表达，并在体内增加整合素活性的上皮脱落的程度。因此，这些研究不仅将探索整合素活性调节，但将提供一个实质性的和完全新颖的贡献，我们的理解粘膜定植的人类特异性细菌病原体。

Colonization of mucosal surfaces is a key step in the pathogenesis of several microbes. While the pathogens contact the epithelial surface by specific adhesins, the infected cells can respond to the bacterial challenge by detaching from the underlying tissue, a process referred to as exfoliation. How bacteria overcome the exfoliation response of mucosal epithelia is unknown. We have previously observed that contact of human epithelial cells with several pathogenic bacteria leads to enhanced integrin activity and substrate-binding of the infected eukaryotic cells preventing their detachment from the extracellular matrix in vitro. This host response depends on the presence of human CEA-related cell adhesion molecules (CEACAMs) on the eukaryotic cells as well as CEACAM-binding adhesins on the side of the bacteria and requires CEACAM-initiated de novo expression of CD105. In this research proposal we will dissect the molecular mechanism that links CD105 expression to the regulation of integrin activity. Furthermore, we will apply a newly established humanized mouse model to evaluate the extent of epithelial exfoliation in the face of bacterial CEACAM engagement, CD105 expression, and increased integrin activity in vivo. Accordingly, these investigations will not only explore integrin activity regulation, but will provide a substantial and completely novel contribution to our understanding of mucosal colonization by human-specific bacterial pathogens.