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

粘膜表面定植是几种微生物致病过程中的关键步骤。虽然病原体通过特定的粘附素接触上皮表面，但受感染的细胞可以通过从底层组织分离来响应细菌的挑战，这一过程被称为剥离。细菌如何克服粘膜上皮的脱落反应尚不清楚。我们以前观察到，人上皮细胞与几种致病菌接触后，感染的真核细胞的整合素活性和底物结合增强，防止它们在体外脱离细胞外基质。这种宿主反应依赖于真核细胞上人CEA相关细胞黏附分子(CEACAM)的存在以及细菌一侧CEACAM结合粘附素的存在，并要求CEACAM启动CD105的从头表达。在这项研究中，我们将剖析CD105表达与整合素活性调节之间的分子机制。此外，我们将应用一个新建立的人源化小鼠模型来评估面对细菌CEACAM参与、CD105表达和体内整合素活性增加时上皮脱落的程度。因此，这些研究不仅将探索整合素活性的调节，而且将为我们理解人类特有的细菌病原体的粘膜定植提供实质性和全新的贡献。

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.