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Von Willebrand Factor Facilitates Intravascular Dissemination of Microsporidia Encephalitozoon hellem.

ABSTRACT: Microsporidia are a group of spore-forming, fungus-related pathogens that can infect both invertebrates and vertebrates including humans. The primary infection site is usually digestive tract, but systemic infections occur as well and cause damages to organs such as lung, brain, and liver. The systemic spread of microsporidia may be intravascular, requiring attachment and colonization in the presence of shear stress. Von Willebrand Factor (VWF) is a large multimeric intravascular protein and the key attachment sites for platelets and coagulation factors. Here in this study, we investigated the interactions between VWF and microsporidia Encephalitozoon hellem (E. hellem), and the modulating effects on E. hellem after VWF binding. Microfluidic assays showed that E. hellem binds to ultra-large VWF strings under shear stress. In vitro germination assay and infection assay proved that E. hellem significantly increased the rates of germination and infection, and these effects would be reversed by VWF blocking antibody. Mass spectrometry analysis further revealed that VWF-incubation altered various aspects of E. hellem including metabolic activity, levels of structural molecules, and protein maturation. Our findings demonstrated that VWF can bind microsporidia in circulation, and modulate its pathogenicity, including promoting germination and infection rate. VWF facilitates microsporidia intravascular spreading and systemic infection.

SUBMITTER: Bao J

PROVIDER: S-EPMC8176104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy.

Project description:Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.

| S-EPMC6053440 | biostudies-literature

Encephalitozoon hellem

Project description:Microsporidian parasite causing keratoconjunctivitis in immunosuppressed patients

| PRJNA53983 | ENA

Refrigeration-Induced Binding of von Willebrand Factor Facilitates Fast Clearance of Refrigerated Platelets.

Project description:OBJECTIVE:Apheresis platelets for transfusion treatment are currently stored at room temperature because after refrigeration platelets are rapidly cleared on transfusion. In this study, the role of von Willebrand factor (VWF) in the clearance of refrigerated platelets is addressed. APPROACH AND RESULTS:Human and murine platelets were refrigerated in gas-permeable bags at 4°C for 24 hours. VWF binding, platelet signaling events, and platelet post-transfusion recovery and survival were measured. After refrigeration, the binding of plasma VWF to platelets was drastically increased, confirming earlier studies. The binding was blocked by peptide OS1 that bound specifically to platelet glycoprotein (GP)Ib? and was absent in VWF-/- plasma. Although surface expression of GPIb? was reduced after refrigeration, refrigeration-induced VWF binding under physiological shear induced unfolding of the GPIb? mechanosensory domain on the platelet, as evidenced by increased exposure of a linear epitope therein. Refrigeration and shear treatment also induced small elevation of intracellular Ca2+, phosphatidylserine exposure, and desialylation of platelets, which were absent in VWF-/- platelets or inhibited by OS1, which is a monomeric 11-residue peptide (CTERMALHNLC). Furthermore, refrigerated VWF-/- platelets displayed increased post-transfusion recovery and survival than wild-type ones. Similarly, adding OS1 to transgenic murine platelets expressing only human GPIb? during refrigeration improved their post-transfusion recovery and survival. CONCLUSIONS:Refrigeration-induced binding of VWF to platelets facilitates their rapid clearance by inducing GPIb?-mediated signaling. Our results suggest that inhibition of the VWF-GPIb? interaction may be a potential strategy to enable refrigeration of platelets for transfusion treatment.

| S-EPMC5699930 | biostudies-literature

Unraveling von Willebrand factor deficiency.

Project description: Not available

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| S-EPMC7948283 | biostudies-literature

von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

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| S-EPMC3856360 | biostudies-literature

Effect of von Willebrand factor on gene expression in HUVECs

Project description:Von Willebrand factor is a paracrine/autocrine regulator of human mesenchymal stem cell adhesion to distressed/apoptotic endothelial cells. This data set examines effect of vWF on gene expression in HUVECs.

2010-11-10 | GSE19816 | GEO

Intracellular storage and regulated secretion of von Willebrand factor in quantitative von Willebrand disease.

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| S-EPMC3129199 | biostudies-literature

Improving diagnosis of von Willebrand disease: Reference ranges for von Willebrand factor multimer distribution.

Project description:BackgroundPhenotypic von Willebrand disease (VWD) classification requires multiple tests including analysis of multimeric distributions von Willebrand factor (VWF) and evaluation of its structure. VWF multimer analysis is labor intensive, nonstandardized, and limited to specialized laboratories. A commercial semiautomatic assay, HYDRAGEL VW multimer assay (H5/11VWM, Sebia), has become available.ObjectivesEstablishment of reference ranges for H5/11VWM to improve VWD classification.MethodsImplementation validation, establishment and validation of normal and pathological reference intervals (NRIs/PRIs), comparison with in-house method using 40 healthy volunteers and 231 VWD patients.ResultsQualitative and quantitative validation of NRI obtained sensitivity of 88% and 79%, respectively, for type 2. Comparison of the two methods showed an overall concordance of 86% with major conflicting results in all atypical 2B (n = 7) and 50% 2M-GPIb (n = 41) showing quantitative and qualitative multimeric loss, that was not detected with in-house method. We were able to use established PRIs, with 73% validity in type 2 cases, to distinguish individual type 2A subtypes (IIA, IIC, IID, IIE) from 2M and 2B.ConclusionH5/11VWM could be used for all clinical purposes because its reliability and its rapid and accurate diagnostic ability and reduced observer bias. Although H5/11VWM cannot evaluate triplet structures, we were able to define 2A subtypes by stripping back to the percentage of intermediate/high-molecular-weight multimers. H5/11HWM could be an efficient and widely available alternative for the "gold standard" technique.

| S-EPMC7443431 | biostudies-literature

Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients.

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| S-EPMC6524857 | biostudies-literature

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