Dataset Information

Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors.

ABSTRACT: Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that an IgSF domain in β represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessment revealed that this newly identified IgI3 fold is not exclusively present in GBS but is predicted to be present in adhesins from other clinically important human pathogens. In agreement with this prediction, we found that CEACAM1 binds to an IgI3 domain found in an adhesin from a different streptococcal species. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.

SUBMITTER: van Sorge NM

PROVIDER: S-EPMC8013792 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors.

van Sorge Nina M NM Bonsor Daniel A DA Deng Liwen L Lindahl Erik E Schmitt Verena V Lyndin Mykola M Schmidt Alexej A Nilsson Olof R OR Brizuela Jaime J Boero Elena E Sundberg Eric J EJ van Strijp Jos A G JAG Doran Kelly S KS Singer Bernhard B BB Lindahl Gunnar G McCarthy Alex J AJ

The EMBO journal 20210201 7

Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria to epithelial surfaces. GBS adhesins have been identified to bind extracellular matrix components and cellular receptors. However, several putative adhesins have no host binding partner characterised. We report here that surface-expressed β protein of GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the ...[more]

PMID: 33522633

Similar Datasets

Project description:BackgroundCEACAM1 in leukocytes controls cell activation during inflammation. This and its expression in epithelial cells led to frequent independent appropriation of CEACAM1 as receptor by pathogens in humans and other species to gain host access and to downregulate its immune response. As a countermeasure, decoy receptors with CEACAM1-like pathogen-binding domains evolved. The granulocyte-specific human CEACAM3 endocytic receptor diverts CEACAM1-binding pathogens to neutrophils for internalization and destruction. The role of the glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 which can also bind CEACAM1-targeting pathogens in humans is less clear.MethodsWe analyzed the selection of CEACAMs to avoid pathogen binding and to maintain similarity between pathogen receptors and decoy receptors in 148 primate species.ResultsNotably, functional CEACAM3 genes were not found in gibbons and New World monkeys. Interestingly, CEACAM6 in these primates exhibits similar high ratios of rates of nonsynonymous and synonymous substitution (dN/dS) in their pathogen-binding N domain exons as found for CEACAM1. High dN/dS ratios are indicative of selection for diversification typically seen in pathogen receptors. Human CEACAM6 is expressed on granulocytes and epithelial cells. Therefore, CEACAM6 could substitute for the missing endocytic receptor CEACAM3. In nearly all investigated primate groups also N exons of the epithelially expressed CEACAM5 exhibit selection for diversification. In African populations, five high-frequency polymorphisms are observed in the pathogen-binding region of CEACAM5 (I80V, V83A, I100T, I112V, I113T) with 3-4 polymorphisms combined in the same individual. These polymorphisms correspond to CEACAM1 pathogen-binding domain sequences.ConclusionThe glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 are under selection to maintain similarity to the pathogen receptor CEACAM1 in most primate species, indicating a function as decoy receptors.

Project description:Background: T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG's crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided. Methods: Two novel CARs targeting the CD19 antigen where the IgG1-CH2 and -CH3 domains were replaced with Ig-like domains from signal-regulatory protein α (SIRPα) were designed in silico. An IgG1-based CAR and a CAR lacking both SIRPα and IgG1 domains were used as comparators. The phenotype and memory phenotype of the expanded cells were analyzed by flow cytometry, and CAR T cell activation and cytotoxic efficacy were assessed in co-culture experiments in response to CD19+ target cells. Unwanted interactions with FcR-expressing myeloid cells were interrogated in co-culture assays with THP-1 monocytic cells. Results: T cells carrying the novel SIRPα-based CARs enacted potent in vitro cytotoxicity against CD19 positive B-lineage leukemia cells, comparable to traditional IgG1-based CAR T cells. Co-culture of IgG1-based CAR T cells with FcR-expressing THP-1 monocytic cells led to prominent cell surface expression of CD69 on T cells together with production of Interleukin (IL)-2 and Interferon-γ, and production of IL-1β, indicating activation of the T cells and monocytes, respectively. Longer co-culture led to killing of the monocytes. No signs of T cell nor monocyte activation were detected in co-cultures of SIRPα-based CAR T cells with THP-1 cells. Arming T cells with the SIRPα-based CARs favored differentiation towards CD4+ phenotype during expansion, while the effects on memory phenotype of the T cells were equivalent between the SIRPα- and IgG1-based CARs. In a pilot experiment, T cells modified with one of the SIRPα-based CARs showed dose dependent leukemia cell control. Conclusion: The novel SIRPα based spacers offer a suitable backbone for developing chimeric antigen receptors that evade the off-target binding to FcR while the cells retain a favorable memory phenotype and efficient cytotoxicity, establishing a promising candidate for future in vivo and clinical testing.

Dataset Information

Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors.

Publications

Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets