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Structural and functional analysis of the interaction between the human microbiota and CEACAMs

Structural and functional analysis of the interaction between the human microbiota and CEACAMs

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BONSIGNORE, Patrizia, 2021. Structural and functional analysis of the interaction between the human microbiota and CEACAMs [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Bonsignore2021Struc-54046, title={Structural and functional analysis of the interaction between the human microbiota and CEACAMs}, year={2021}, author={Bonsignore, Patrizia}, address={Konstanz}, school={Universität Konstanz} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/54046"> <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/> <dcterms:issued>2021</dcterms:issued> <dc:language>eng</dc:language> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:rights>terms-of-use</dc:rights> <dcterms:title>Structural and functional analysis of the interaction between the human microbiota and CEACAMs</dcterms:title> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>Bonsignore, Patrizia</dc:contributor> <dcterms:abstract xml:lang="eng">The human body represents an excellent ecological niche for a versatile community of microbes such as bacteria, archaea, fungi, and protozoa. Besides commensal and mutualistic residing microorganisms, pathogens regularly attempt colonization, for which they have developed diverse strategies to gain foothold in the human host. One strategy involves a subgroup of the immunoglobulin super family: carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). Epithelial members of the surface expressed CEACAM proteins serve as receptors for certain pathogens such as Neisseria gonorrhoeae, Haemophilus influenzae, or Helicobacter pylori. Remarkably, severe diseases caused by those pathogens occur rarely due to a sophisticated defense provided by the same protein family: the neutrophil granulocyte-expressed innate immune receptor CEACAM3. CEACAM3 recognizes CEACAM-binding pathogens and initiates a rapid, opsonin-independent clearance. In this work we provide an overview of the state of the art with respect to CEACAM3, including its structure, functions and evolutionary background (Chapter I). Subsequently, we focus on the evolution of CEACAM3 within the primate lineage. We analyze genomes of higher primates identifying new CEACAM3 orthologs. Comparison of primate CEACAM3 genes reveal an extremely fast evolving extracellular domain, whereas the intracellular signal transducing part appears to be conserved. Testing the ability of different primate CEACAM3 variants to recognize human restricted pathogens demonstrates decreasing binding affinity with increasing phylogenetic distance. Exchanging single amino acids in gorilla CEACAM3 towards human CEACAM3 reestablish recognition of the pathogen Haemophilus aegyptius. Remarkably, several pathogens, such as Haemophilus influenzae or Neisseria gonorrhoeae exhibit adhesins that target CEACAM1, but circumvent recognition by the highly similar IgV-like domain of CEACAM3. We unveil a single amino acid variation between both receptors that is crucial for CEACAM1 binding, but prevents CEACAM3 association in Neisseria gonorrhoeae. An additional mutation at another site within the extracellular domain of CEACAM3 allows the reestablishment of Haemophilus influenzae recognition by the adapted CEACAM3 variant. Interestingly, a human CEACAM3 polymorphism exhibiting these amino acid alterations is found in around 40% of the African population. The selection for CEACAM3 variants with an extended binding spectrum demonstrates ongoing adaptation and counter-adaptation between pathogen and host (Chapter II). Recognition by CEACAM3 and interaction with epithelial CEACAMs is not exclusively found in bacteria, but is also observed for the opportunistic pathogenic yeast Candida albicans. By breaching the mucosal barrier and causing local and systemic infections (Candidiasis), this organism constitutes a serious threat to the health of the human host. We are interested in whether the innate immune receptor CEACAM3 might play a part in defense mechanisms against C. albicans. In our study, binding assays reveal that CEACAM3 is able to recognize a broad range of yeasts, which underlines the exceptional protective spectrum of this immune receptor. We observe that CEACAM interaction is depended on growth conditions of Candida such as iron limitation or the presence of serum, as commonly experienced for tissue infiltrating microbes. Interestingly, Candida is only recognized by human CEACAM3 and the closely related chimpanzee CEACAM3 but not by other primate orthologs, indicating a more recent evolutionary development. Still, the proteinaceous adhesin of Candida involved in CEACAM-binding remains elusive. Presumably this adhesin activates the innate immune receptor CEACAM3 and causes intracellular receptor tyrosine phosphorylation but does not result in CEACAM3-dependent uptake. Together, these results implicate CEACAM3 in the recognition and activation of downstream signalling following yeast-binding to host phagocytes (Chapter III). Each mammalian species has its own characteristic microbiota that is shaped by two major factors: nutrition and host genetics. While the influence of diet has been studied extensively, we aim to investigate the role of host genetics in regard to microbial compositions, by putting members of the CEACAM family in centre of our study. CEACAMs are exploited by human-restricted pathogens for host colonization and have a high diversification in mammals, therefore representing a suitable host-specific factor that could help to shape a characteristic microbiota. In our study, CEACAM-associating commensal gut bacteria are enriched from human stool samples and identified using 16S rRNA gene pyrosequencing. Although the CEACAM-binding spectrum of these commensals is as versatile as their phylogenetic origin, they all bind to CEA, a CEACAM member exclusively expressed in epithelial cells. Interestingly, bacterial species that are preferentially found in humans show restriction to human CEACAMs. In contrast, Enterococcus faecalis, known to colonize not only human but also mouse intestine, possesses a broadened binding spectrum that also comprises other mammalian CEACAM proteins. Infection of cells with and without CEACAM-expression reveals no difference in bacterial interaction on cellular surfaces, suggesting a minor contribution during early colonization events. However, fluorescently labeled sugar residues derived from the highly glycosylated CEACAM molecules can be recovered in E. faecalis proteins after CEACAM interaction. We suggest that CEACAMs may not be involved in early cell surface association processes, but that microbe interaction with host-specific CEACAM proteins and subsequent degradation of linked carbohydrate moieties could support long-term colonization by providing an additional docking site and energy source. In this way, CEACAM molecules could contribute to the formation of a host characteristic microbial community (Chapter IV). Altogether, this study provides insight into the complex interplay between pathogens, host, and the commensal microbiota using the example of the CEACAM family.</dcterms:abstract> <dc:creator>Bonsignore, Patrizia</dc:creator> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54046/3/Bonsignore_2-do653ljvzumu2.pdf"/> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/54046"/> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-06-22T07:37:27Z</dcterms:available> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54046/3/Bonsignore_2-do653ljvzumu2.pdf"/> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-06-22T07:37:27Z</dc:date> </rdf:Description> </rdf:RDF>

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