Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here we identified members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as novel receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1 mediated signaling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells, and enhances the release of proinflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibodymediated abrogation of the HopQ function shows. Together, our data imply the HopQ-CEACAM1 interaction as potentially promising novel therapeutic target to combat H. pyloriassociated diseases. Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens, colonizing half of the world's population. Chronic inflammation elicited by this bacterium is the main cause of gastric cancer 1. During co-evolution with it's human host over more than 60.000 years 2 , the bacterium has acquired numerous adaptations for the long-term survival within its unique niche, the stomach. This includes the ability to buffer the extreme acidity of this environment, the interference with cellular signaling pathways, the evasion of the human immune response and a strong adhesive property to host cells 3. Specifically, H. pylori persistence is facilitated by the binding of BabA and SabA adhesins to the human blood group antigen Leb and the sLex antigen, respectively 4-6. However, adhesion to blood group antigens is not universal, is dynamically regulated during the course of infection and can also be turned off 7. We observed that H. pylori was capable of binding to human gastric epithelium of nonsecretors. Therefore, we hypothesized that the bacterium might be able to interact with other cell surface receptors to ensure persistent colonization. We here show that the H. pylori adhesin HopQ specifically interacts with human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). CEACAMs embrace a group of immunoglobulin superfamily-related glycoproteins with a wide tissue distribution. CEACAM1 can be expressed in leukocytes, endothelial and epithelial cells, CEACAM3 and CEACAM8 in granulocytes, CEACAM5 and CEACAM7 in epithelial cells and CEACAM6 in epithelia and granulocytes. In epithelial cells, transmembrane anchored CEACAM1 as well as glycosylphosphatidylinositol-linked CEACAM5, CEACAM6 and CEACAM7 localize to the apical membrane 8. CEACAMs modulate diverse cellular functions such as cell adhesion, differentiation,...

SUMMARY The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood-group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive but binding is restored by pH neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions; changes during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA’s extraordinary reversible acid-responsiveness enables tight mucosal bacterial adherence while at the same time allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutations and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, and BabA’s adaptive evolution contributes importantly to H. pylori persistence and to overt gastric disease.

BackgroundChronic neuroinflammation is a hallmark of Parkinson’s disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer’s disease. This is the first report on the co-aggregation of α-synuclein (α-syn) and S100A9 both in vitro and ex vivo in PD brain.MethodsSingle and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and α-syn location and aggregation. In vitro studies revealing S100A9 and α-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods.ResultsCo-localized and co-aggregated S100A9 and α-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4–6). Lewy bodies were characterized by ca. 10–23 μm outer diameter, with S100A9 and α-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and α-syn were shown to interact with each other via the α-syn C-terminus with an apparent dissociation constant of ca. 5 μM. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of α-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers.ConclusionsWe suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving α-syn and S100A9 and leading to PD, similar to the effect of S100A9 and Aβ co-aggregation in Alzheimer’s disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1210-9) contains supplementary material, which is available to authorized users.

Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer’s disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to Aβ and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without Aβ. S100A9 and Aβ plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ(1-42) and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ(1-42) levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ(1-42) and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

The original version of this Article contained incorrect labels in Figs 3b and 4e. In Fig. 3b, the second western blot panel should have been labelled 'CEACAM1'. In Fig. 4e, the final two values on the y axis should have read 'I91A' and 'I91T'. All versions of the Article have been updated. We apologize for any confusion this may have caused.

Complementary experimental techniques were applied to characterize bioapatite nanocrystals from pathological cardiovascular deposits. The investigated collection included the leaflets from aortic valve, leaflets from mitral valve, leaflets from tricuspid valve and calcified aorta's wall. XRD, EDX and FTIR data have shown that all studied samples consist of imperfect apatite with different crystallinity and variable chemical composition. In accordance with TEM data, the crystals of pathological calcified deposits frequently have oblong or rod‐like shape (length of 60‐90 nanometers, width of 20‐30 nanometers). At the same time, in the SEM and TEM experiments, the complex spheroid assemblies and planar sheet‐like shaped formations with crystal structure close to apatite were observed. Probably, the different shape and morphology of the particles are caused by different ways of crystal nucleation and growth, although the exact mechanisms remain an open question.

Triply periodic minimal surfaces (TPMS) are known for their advanced mechanical properties and are wrinkle-free with a smooth local topology. These surfaces provide suitable conditions for cell attachment and proliferation. In this study, the in vitro osteoinductive and antibacterial properties of scaffolds with different minimal pore diameters and architectures were investigated. For the first time, scaffolds with TPMS architecture were treated electrochemically by plasma electrolytic oxidation (PEO) with and without silver nanoparticles (AgNPs) to enhance the surface bioactivity. It was found that the scaffold architecture had a greater impact on the osteoblast cell activity than the pore size. Through control of the architecture type, the collagen production by osteoblast cells increased by 18.9% and by 43.0% in the case of additional surface PEO bioactivation. The manufactured scaffolds demonstrated an extremely low quasi-elastic modulus (comparable with trabecular and cortical bone), which was 5 -10 times lower than that of bulk titanium (6.4-11.4 GPa vs 100-105 GPa). The AgNPs provided antibacterial properties against both gram-positive and gram-negative bacteria and had no significant impact on the osteoblast cell growth. Complex experimental results show the in vitro effectiveness of the PEO-modified TPMS architecture, which could positively impact the clinical applications of porous bioactive implants.