CEACAM1-mediated intenalization of Neisseria gonorrhoeae into mammalian cells


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BACHMANN, Verena, 2010. CEACAM1-mediated intenalization of Neisseria gonorrhoeae into mammalian cells [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Bachmann2010CEACA-7693, title={CEACAM1-mediated intenalization of Neisseria gonorrhoeae into mammalian cells}, year={2010}, author={Bachmann, Verena}, note={Teilw. erschienen in: Cellular Microbiology ; 10 (2008). - S.1074-1092 und auch erschienen in: Science ; 329 (2010). - 5996. - S.1197-1201}, address={Konstanz}, school={Universität Konstanz} }

2011-03-24T17:36:26Z 2012-12-15T23:25:04Z Bachmann, Verena Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) belongs to the immunoglobulin superfamily and represents a multifunctional receptor involved in various physiological processes, including cell differentiation, insulin metabolism, angiogenesis and immune cell function. CEACAM1 has the widest tissue distribution of all CEACAM-family members and is expressed on epithelial, endothelial, and hematopoietic cells. Interestingly it also serves as a receptor for human specific pathogens, like Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Neisseria meningitidis and Neisseria gonorrhoeae. N. gonorrhoeae is characterized as a highly adapted human pathogen and the engagement of different CEACAMs via its Opa proteins demonstrates a critical step in the infection process and the colonization of mucosal surfaces. This interaction initiates several cellular signalling cascades resulting in the internalization of the pathogen. In this study, we analyzed the mechanism of CEACAM1-mediated internalization of OpaCEA-expressing Neisseria gonorrhoeae in detail. CEACAM-mediated contact of the gonococci also triggers de-novo expression of CD105. We could demonstrate in vivo, that the suppression of exfoliation is based on the interaction of CD105 with the focal adhesion protein zyxin and the resulting activation of integrins. In a humanized mouse model we could show for the first time the importance of exfoliation during the colonization of the host´s mucosa and a new molecular mechanism for suppression of exfoliation by bacteria could be revealed.<br />Surprisingly, the neisserial engagement of CEACAM1 via its Opa proteins and the subsequent internalization of the pathogen are completely independent of the cytoplasmic domain of the receptor. By comparison of wildtype CEACAM1 and a CEACAM1 mutant lacking the cytoplasmic domain, we could demonstrate an equivalent internalization of different human pathogens. In contrast to CEACAM3-mediated internalization the uptake is only to a minor degree dependent on actin dynamics and instead requires the integrity of membrane microdomains. We demonstrated that the transmembrane domain of CEACAM1 is responsible for its association with ganglioside- and cholesterol-enriched microdomains after neisserial engagement. By applying different transmembrane chimeras of CEACAM1 and CEACAM3, we could show that the close proximity of two phenylalanine residues in the transmembrane domain of CEACAM1 is critical for membrane microdomain localization. We could further show that the internalization of N. gonorrhoeae depends on the integrity of membrane microdomains and the presence of caveolin1 resulting in a non-classical endocytotic pathway. Also a functional role for microtubules, RhoG, Rac1 and phosphoinositide-3-kinase (PI3K) could be demonstrated.<br />In summary, the data obtained from this study provide an advanced view on the CEACAM1-mediated internalization process of Neisseria gonorrhoeae and display a novel scenario for the successful colonization of the human mucosa by highly adapted pathogens. 2010 Bachmann, Verena deu application/pdf terms-of-use CEACAM1-mediated intenalization of Neisseria gonorrhoeae into mammalian cells

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