RARE DISEASE
Hemolytic uremic syndrome
Hemolytic uremic syndrome
Hemolytic uremic syndrome
Synonyms: HUS
Synonyms: HUS
Synonyms: HUS
Drug discovery
2
drugs
With orphan designations
Overview
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Most cases (90%) are caused by Shiga toxin-producing E. coli (STEC), while 10% are atypical (aHUS) due to complement dysregulation or other triggers [1][5][6]. Organ involvement includes renal failure (61% requiring dialysis), neurologic complications (52% in adults), and cardiovascular damage [9][16].
Burden
Acute mortality: 5% in children vs. 19.8% in adults (higher with immunodeficiency/severe neurology) [9][16]
Chronic sequelae: 25–45% develop hypertension or CKD; 3–5% progress to ESRD [4][10][16]
Economic impact: $541,695/case (direct/indirect costs), including long-term renal/psychosocial care [4][9]
Therapies
STEC-HUS: Supportive care (IV rehydration, transfusion, dialysis), avoidance of antibiotics/antidiarrheals [3][6][8]
aHUS: Complement inhibitors (eculizumab/ravulizumab) with 80% efficacy; plasma exchange for refractory cases [5][6][18]
Renal replacement therapy required in 50–63% of patients; transplant considered for end-stage disease [8][10]
Categories: rare renal diseases, rare transplant-related disorders
Research Papers
2,287 drug discovery papers about Hemolytic uremic syndrome, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,287 drug discovery papers about Hemolytic uremic syndrome, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Gypenosides Mitigate STEC-Induced Intestinal Injury Through Modulation of Ferroptosis Involving the ATF4-CHAC1-GPX4 Axis.
Shiga toxin-producing Escherichia coli (STEC) infection causes severe enteropathies and hemolytic uremic syndrome, yet non-antibiotic therapeutic strategies remain limited. This study evaluated whether gypenosides (GPs) protect against STEC-induced intestinal injury and investigated the underlying mechanisms. Mice were pretreated with GPs prior to STEC challenge, and protective effects were comprehensively assessed through survival analysis, bacterial burden quantification, transcriptomic profiling, flow cytometry, electron microscopy, and Western blotting. GPs significantly improved survival rates, alleviated diarrheal symptoms, reduced bacterial dissemination in systemic organs, and lowered Stx2 toxin levels. Furthermore, GPs effectively restored gut microbiota dysbiosis by enriching beneficial bacterial genera. Transcriptomic analysis suggested that GP treatment was associated with suppression of ferroptosis-related signaling pathways. Ultrastructural examination demonstrated ameliorated mitochondrial vacuolization, and biochemical assays confirmed decreased Fe2+ accumulation and attenuated lipid peroxidation. Mechanistically, these changes were associated with modulation of the ATF4-CHAC1-GPX4 axis and suppression of ferroptosis, together with preservation of mitochondrial integrity. Collectively, these findings identify GPs as a promising protective candidate against STEC-induced intestinal injury and highlight the ATF4-CHAC1-GPX4 axis as a candidate pathway for further mechanistic investigation.
2026-09-25 | Complement diagnostics and therapeutics for the pediatric population: early successes and opportunities for further advancement.
Complement-mediated diseases are individually rare, often rapidly progressive, and historically associated with high rates of permanent organ injury or death but are now among the most therapeutically actionable conditions in pediatric nephrology, hematology, and rheumatology. As demonstrated by thrombotic microangiopathy, and hemolytic uremic syndrome in particular, diagnostic delay can contribute directly to irreversible kidney injury. Complement inhibition has substantially improved outcomes in these conditions that previously carried a substantial risk of end-stage kidney disease. This review addresses the complement system as a clinical and therapeutic framework for the practicing pediatric clinician. The pathophysiology of the major complement-mediated diseases affecting children is examined, with atypical hemolytic uremic syndrome and transplant-associated thrombotic microangiopathy as central disease models alongside paroxysmal nocturnal hemoglobinuria, C3 glomerulopathy, IgA nephropathy, and ANCA-associated vasculitis. Approved complement inhibitors are reviewed by mechanistic position in the cascade, with attention to the clinical implications of terminal versus proximal pathway inhibition. Laboratory diagnosis, monitoring, and assessment of complement blockade adequacy are addressed, including practical limitations of complement testing in clinical practice. Critical gaps are examined, including diagnostic delays, absent validated biomarkers, inadequate pediatric trial infrastructure, and conditions without targeted therapies. Emerging therapeutics, point-of-care diagnostics, and pediatric-specific considerations including transition of care and reproductive counseling complete the review. Complement therapeutics have meaningfully altered the trajectory of some of the most severe and inadequately treated pediatric diseases. This field continues to evolve rapidly, with expanding indications and novel agents, though drug development challenges, diagnostic and monitoring gaps, and equitable consideration of pediatric application of these novel agents remain essential priorities.
2026-09-13 | The antibiotic NAB815 does not induce SOS response and toxin production in Shiga toxin-producing Escherichia coli at sub-bactericidal concentrations.
Hemolytic uremic syndrome (HUS) is a rare but severe clinical condition, primarily caused by Shiga toxin-producing Escherichia coli (STEC) infections. A critical early step in the pathogenesis of HUS is the entry of Shiga toxins (Stx) into the bloodstream, where they interact with circulating blood cells via globotriaosylceramide (Gb3Cer) and Toll-like receptor 4 (TLR4). This triggers the release of Stx-containing extracellular vesicles (EV), a critical late step for HUS onset. Currently, there are no specific therapeutic interventions for HUS, and the management of STEC-infected patients is largely supportive. Antibiotics are generally avoided due to the risk of inducing the bacterial SOS response thereby enhancing Stx phage activation and toxin production. Recently, our group developed NAB815, a polymyxin B derivative capable of inhibiting Stx2a binding to TLR4, thereby reducing the release of Stx-containing EV and enhancing survival in cellular and animal models. However, as NAB815 is an antibiotic, it is unclear whether it might also have an undesirable impact on Stx production via phage activation. Here, we demonstrate that exposure of reporter or wild type clinical STEC strains to NAB815 neither triggered the SOS response nor increased Stx1 or Stx2 amounts. These results indicate that NAB815 may mitigate Stx-mediated toxicity without having an off-target effect on Stx phage activation, supporting its potential as a safe therapeutic intervention for STEC patients.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
2026-08-26 | Recurrent Postpartum Atypical Hemolytic Uremic Syndrome Caused by a C3 Pathogenic Variant: A Case Report.
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy (TMA) driven by uncontrolled activation of the complement alternative pathway. Pregnancy and postpartum period are well-recognized triggers for aHUS. In recent years, the prognosis of aHUS has substantially improved with the use of complement-targeted therapies. However, timely recognition, accurate classification, and prompt treatment initiation remain critical. This report describes a case of postpartum aHUS caused by a C3 gene mutation that achieved complete clinical and laboratory remission following a treatment strategy that included early eculizumab, plasma infusion, and renal replacement therapy. Drawing on the literature, we discuss key diagnostic and therapeutic considerations as well as clinical implications to provide guidance for clinical practice. We present a 35-year-old multiparous woman (gravida 3, para 3) who developed acute kidney injury, microangiopathic hemolytic anemia, and severe thrombocytopenia 2 days after cesarean section. She had a history of similar TMA episode 8 years postpartum. Laboratory investigations showed normal ADAMTS13 activity, negative autoimmune antibodies, reduced serum complement C3 and factor I levels, and elevated sC5b-9. Whole-exome sequencing identified a heterozygous pathogenic mutation in the C3 gene: c.1774C>T (p.R592W). Eculizumab was initiated within 24 hours of clinical suspicion, combined with plasma infusion and renal replacement therapy. The patient achieved complete clinical and laboratory remission: renal function, platelet count, hemoglobin, and lactate dehydrogenase returned to normal within 4 weeks. She remained stable during long-term follow-up on maintenance eculizumab. This case is particularly instructive because the patient had a prior TMA episode that was retrospectively suggestive of aHUS following genetic confirmation; however, definitive reclassification could not be established with certainty due to the lack of genetic testing at that time. This case highlights that C3 variant-mediated aHUS can be repeatedly triggered by pregnancy. Early recognition, prompt initiation of C5 inhibition, and multidisciplinary care are critical for renal recovery and favorable outcomes. Clinicians should distinguish postpartum aHUS from preeclampsia, HELLP syndrome, and TTP to prevent treatment delay.
cell therapies
2026-09-01 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center.
Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-08-31 | Pathogenesis and therapeutic strategies in the interaction between gut microbiota and enterohemorrhagic Escherichia coli infection.
Enterohemorrhagic Escherichia coli (EHEC) is a major foodborne pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. Increasing evidence indicates that the gut microbiota plays a central role in modulating EHEC pathogenesis through complex metabolic and signaling networks. Beneficial commensals, including Bifidobacterium, Lactobacillus, and segmented filamentous bacteria, contribute to colonization resistance by competing for nutrients and adhesion sites, producing antimicrobial metabolites, and enhancing epithelial barrier integrity. In contrast, certain species such as Bacteroides thetaiotaomicron and Enterococcus faecalis may promote EHEC virulence by altering intestinal nutrient availability or triggering the expression of virulence genes. Microbiota-derived metabolites, including short-chain fatty acids, succinate, indole, riboflavin, nicotinamide, ethanolamine, and L-malate, act as important regulatory signals that connect microbial metabolism with LEE-mediated virulence pathways. Understanding these host-microbe-pathogen interactions provides a mechanistic basis for developing microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation that enhance colonization resistance and attenuate virulence. Integration of AI-based analytics with multi-omics approaches is expected to facilitate the design of personalized, mechanism-driven therapeutic strategies for the control of EHEC infection.
2026-08-19 | Surface Functionalization of Small Extracellular Vesicles Derived from Caco-2 and HEK293T Cells in the Neutralization of Shiga Toxin 1 Subunit B.
Shiga toxins (Stx) are key virulence factors of Shiga toxin-producing Escherichia coli (STEC), which are responsible for severe foodborne infections that can progress to hemolytic-uremic syndrome (HUS). Currently, no specific antitoxin therapies are available. In this study, we devised a glycoengineering strategy utilizing Functional-Spacer-Lipid (FSL) conjugates to create small extracellular vesicles (sEVs)-based decoy receptors for Shiga toxin type 1 (Stx1). sEVs isolated from human Caco-2 and HEK293T cells were functionalized with Gb3 trisaccharide (Galα1→4Galβ1→4Glc)-containing FSL conjugates, yielding Gb3-decorated vesicles displaying the Galα1→4Gal epitope. Characterization of FSL-modified sEVs confirmed that FSL incorporation did not adversely affect sEV morphology, size distribution, or surface charge. Western blotting and bead-assisted flow cytometry verified the presence of exosomal markers (CD9 and CD63) and the Gb3 epitope on modified vesicles. Gb3-tagged sEVs from both cell types exhibited high specificity in binding Stx1B, while control vesicles carrying Galili epitope (Galα1→3Galβ1→4GlcNAc), lacking Stx1B binding, demonstrated negligible binding. Gb3-expressing Caco-2 cell-based assays revealed that Gb3-decorated sEVs markedly reduced Stx1B binding to Caco-2 cells, indicating effective competition with cellular receptors. Furthermore, glycoengineered sEVs did not impair Caco-2 cell viability at concentrations sufficient for Stx1B sequestration. These findings establish FSL-mediated glycoengineering as a rapid and versatile approach for generating sEV-based decoy receptors that effectively bind Stx1B. Gb3-containing human sEVs may serve as an agent for neutralizing Stx1B and potentially other glycan-binding toxins, supporting the development of promising next-generation antitoxin therapeutics.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2024-11-18 | Gb3 trisaccharide-bearing exosomes as a novel neutralizer for Shiga toxin type 1.
Shiga toxin types 1 (Stx1) and 2 (Stx2), produced by Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae, are key virulence factors responsible for severe foodborne diseases, such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). The receptors for Stxs are Gb3 and P1 glycotope, which contain the Galα1→4Gal epitope and are synthesized by human α1,4-galactosyltransferase (A4galt). Stx-related infections pose a global public health challenge, owing to the limited therapeutic options due to the restricted use of antibiotics. Therefore, there is an urgent need to develop novel therapeutic strategies. This study proposes an innovative strategy utilizing exosomes derived from CHO-Lec2 cells, which were modified with Functional-Spacer-Lipid (FSL) conjugates bearing the Gb3 carbohydrate epitope (exo-Gb3-FSL). Flow cytometry analysis confirmed the presence of Galα1→4Gal disaccharides on exo-Gb3-FSL constructs, enabling them to bind Stx1. Moreover, using CHO-Lec2 cells evaluated the ability of exo-Gb3-FSL agents to bind Stx1 and protect these cells from Stx1-mediated cytotoxicity. For Stx1-treated CHO-Lec2 cells, increased cell survival was observed when using 25 μM exo-Gb3-FSL constructs, compared to control cells. These findings highlight the potential of exosome-based anti-Stx1 agents as promising alternatives to conventional therapies. This innovative strategy may provide novel directions for studies on Stx1 neutralization, offering a valuable strategy for the treatment of Stx-related diseases.
proteins
2026-08-26 | Inhibitory Effects of Oxysterlina 3, Satanin 1, and Curvicin Cecropins on the Growth and stx2 Gene Expression of Shiga Toxin-Producing Escherichia coli (STEC).
Shiga toxin-producing Escherichia coli (STEC) poses a significant health risk, with Stx1 and Stx2 as key virulence factors associated with hemolytic uremic syndrome (HUS). Current STEC treatment relies on supportive care, avoiding antimicrobial therapy. This study evaluates the antibacterial activity of three cecropin peptides and their effect on the expression of the stx2 gene in STEC. Employing microdilution assays and RT-qPCR, all three cecropins demonstrated antibacterial efficacy, displaying MIC and MBC values of 12.5 µg/mL, and decreased gene expression levels following treatment. Notably, these cecropins not only inhibited STEC growth but also significantly reduced stx2 mRNA expression. These findings underscore the therapeutic potential of cecropins as an alternative treatment for STEC infections and suggest they may mitigate associated complications.
2026-05-05 | Targeting StxB-mediated intracellular trafficking as a pharmacological strategy for anti-virulence intervention.
Shiga toxin (Stx) is a prototypical bacterial toxin responsible for severe diseases such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). Despite extensive research efforts, therapeutic options remain limited, and no approved strategy directly targets its pathogenic mechanism. Shiga toxin belongs to the AB5 family and consists of a catalytically active A subunit (StxA) and a pentameric B subunit (StxB). Importantly, its pathogenicity depends not simply on the enzymatic activity of StxA but critically on the host cell entry and intracellular trafficking mediated by the StxB. Through multivalent binding to the Gb3 receptor, StxB reorganizes membrane microdomains and initiates endocytosis. A substantial fraction of internalized toxin escapes lysosomal degradation and instead exploits the Golgi-endoplasmic reticulum (ER) retrograde transport pathway to enable cytosolic delivery of StxA. This sequence of events constitutes a rate-limiting determinant of toxin pathogenicity and demonstrates that StxB actively orchestrates host intracellular trafficking networks rather than serving merely as a receptor-binding component. In this review, we integrate molecular and biophysical mechanisms of StxB-mediated intracellular trafficking and comparatively evaluate the druggability of each trafficking step. In particular, we reinterpret approaches such as inhibition of toxin binding, disruption of membrane microdomains, blockade of endocytosis, and inhibition of Golgi-ER retrograde transport from the perspective of anti-virulence therapy. We propose that selective modulation of StxB-dependent trafficking bottlenecks represents a conceptually novel therapeutic strategy that can attenuate host damage while reducing the risk of resistance development.
2025-10-05 | Structural characterization of Factor H via computational methods: Implications for disease and therapy.
Complement Factor H (CFH) is a crucial regulator of the alternative complement pathway, maintaining immune balance by preventing excessive activation that damages host tissues. This liver-derived glycoprotein binds to C3b and inhibits C3 convertase formation, with its N-terminal (CCP1-4) and C-terminal (CCP19-20) domains playing key roles in complement regulation and host recognition. In this in silico study, we explored the molecular architecture and interaction landscape of Factor H, identifying highly conserved motifs-particularly in CCP4, CCP8-9, and CCP12, as well as conserved lysine residues across CCP1-4. Motifs 11, 14, and 18 were mapped to the C-terminal domains (CCP18-20). Ligand interaction analysis revealed that heparin binds to CCP2 and CCP15, malondialdehyde binds to CCP3, N-glycoloyl-D-glucosamine to CCP11, and O-sialic acid to CCP11 and CCP12. Additionally, FH was shown to interact with endogenous ligands, including PTX3, fibromodulin, osteoadherin, chondroadherin, prion protein, adrenomedullin, and annexin II. These findings provide deeper insight into FH's role in complement-related disorders, such as aHUS, AMD, and dense deposit disease, supporting its potential as a therapeutic target for precision immune modulation.
2025-05-13 | The 4 functional segments of Factor H: Role in physiological target recognition and contribution to disease.
Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified 4 distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and heparin sites. Three segments are linked to diseases. The regulatory segment is affected in C3 glomerulopathy and antineutrophil cytoplasmic antibody-associated vasculitis. The second segment includes the Y402H polymorphism of age-related macular degeneration, is associated with different types of cancer, and is targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome, in FHR1:FHR3 deficient and autoantibody-positive hemolytic uremic syndrome form and is exploited by pathogens. Factor H function is modulated by Factor H like protein 1 and FHR1, 2 plasma proteins that share segments with Factor H. This interplay is critical for fine-tuning local complement. Understanding Factor H's physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides insights into disease mechanisms and provides opportunities for therapeutic intervention by using full-length Factor H, its fragments, or complement-modulatory compounds.
2025-01-12 | A mutant complement factor H (W1183R) enhances proteolytic cleavage of von Willebrand factor by ADAMTS-13 under shear.
A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood. To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution. We employed recombinant protein expression, purification, and various biochemical and biophysical tools. Purified recombinant W1183R-CFH but not wild-type (WT) CFH protein enhanced the proteolytic cleavage of both peptidyl and multimeric VWF substrates by recombinant ADAMTS-13 in a concentration-dependent manner. Microscale thermophoresis assay demonstrated that both W1183R-CFH and WT-CFH proteins bound various VWF fragments (eg, AIM-A1, A1-A2-A3, D'D3, D'D3-A1, and D'D3-A1-A2) with high affinities. Optical tweezer experiments further showed a concentration-dependent alteration in the contour length (Lc) and the persistent length (Lp) following pulling VWF-A2 domain in the presence of W1183R-CFH or WT-CFH protein. AlphaFold experiments revealed conformational changes in the VWF-A2, particularly the central region where the cleavage bond resides following addition of W1183R-CFH or WT-CFH protein. These results demonstrate for the first time that W1183R-CFH but not WT-CFH protein enhances the proteolytic cleavage of VWF by ADAMTS-13 under shear. This may be achieved by mechanic-induced conformational changes of the central A2 domain, leading to an enhanced cleavage of Tyr1605-Met1606 bond by ADAMTS-13 under pathophysiological conditions.
antibodies
2026-09-26 | TLR4: A Potential Therapeutic Target in the Experimental Pathogenesis of Hemolytic-Uremic Syndrome.
Childhood infections by Shiga toxin (Stx)-producing Escherichia coli (STEC) cause bloody diarrhea and the life-threatening hemolytic-uremic syndrome (HUS). Stx2, produced by STEC in the gut, is released into the bloodstream and interacts with circulating cells (monocytes, neutrophils, and platelets) through two different receptors: Gb3Cer (globotriaosylceramide) and Toll-like receptor 4 (TLR4). Consequently, blood cells form leukocyte/platelet aggregates and release pathogenic Stx2-containing extracellular vesicles (EVs) that, by damaging the kidney, induce the transition from bloody diarrhea to HUS. Human blood was incubated with Stx2 to induce the formation of neutrophil/platelet and platelet-only aggregates (observed in May-Grünwald Giemsa-stained blood smears) and pathogenic blood cell-derived EVs (isolated by size-exclusion chromatography or differential centrifugation) toxic to Vero cells (assessed by a viability assay). In the presence of a monoclonal antibody against TLR4 (anti-TLR4), the formation of neutrophil/platelet and platelet-only aggregates was greatly reduced compared to treatment with Stx2 alone. Moreover, anti-TLR4 significantly decreased the total mass of pathogenic blood cell-derived EVs produced by Stx2 (detected by nanoparticle tracking analysis), which proved less toxic to Vero cells than those produced by Stx2 alone. The impairment of the Stx2-TLR4 axis obtained during the experimental pathogenesis of HUS provides proof-of-concept evidence supporting TLR4 as a potential therapeutic target.
2026-09-25 | Atypical Hemolytic Uremic Syndrome in a Patient With Inflammatory Bowel Disease
Atypical hemolytic uremic syndrome is a life-threatening thrombotic microangiopathy due to complement dysregulation that can be triggered by systemic inflammatory states. We describe a patient with inflammatory bowel disease presenting with pain, melena, and laboratory test results showing hemolytic anemia, thrombocytopenia, and acute kidney injury. Subsequent testing led to a diagnosis of atypical hemolytic uremic syndrome, prompting initiation of eculizumab with rapid improvement in his hemolysis, thrombocytopenia, and acute kidney injury. Providers should maintain a high index of suspicion for uncommon but grave conditions associated with inflammatory bowel disease and consider complement testing if thrombotic microangiopathy is suspected.
2026-09-23 | Atypical Hemolytic Uremic (Ahus) Syndrome with Kidney Injury in Pediatric Patient: A Case Report
Hemolytic uremic syndrome is a form of thrombotic microangiopathy (TMA) which is characterized by thrombocytopenia, microangiopathy hemolytic anemia and renal impairment. Approximately 10% of cases of the hemolytic–uremic syndrome is classified as atypical, since they are not caused by either Stx-producing bacteria or streptococci. Early recognition and initiation of appropriate treatment are essential in patient with a HUS which involves supportive care and inhibition of complement system. Plasmatherapy is recommended as first line treatment approach for aHUS. Timely initiation of plasma exchange, dialysis along with supportive treatment results in gradual improvement in 60- 70% of cases. There are other evolving approaches for the management of a HUS which shows promising results such as anti-C5 monoclonal antibody such as eculizumab, and treating complementary etiology
2026-09-15 | Atypical hemolytic uremic syndrome in kidney transplantation.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder that affects individuals of any age. It is caused by genetic abnormalities of the alternative complement pathway, arising from inherited or de novo mutations, or from acquired factors such as autoantibodies against complement proteins, including complement factor H. Clinically, aHUS is characterized by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. However, its clinical presentation may be difficult to distinguish from typical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. aHUS is driven by uncontrolled activation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis. Atypical HUS may also occur after kidney transplantation, either as recurrence of the native disease or as de novo post-transplant thrombotic microangiopathy. The diagnosis of post-transplant aHUS relies on the presence of the above-mentioned classic triad and the exclusion of secondary causes such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS. The pathophysiology is similar, involving either genetic mutations affecting complement proteins or acquired dysregulation due to autoantibodies. Historically, plasma exchange was used to replace dysfunctional complement regulators and remove circulating autoantibodies, with variable success. After transplantation, the disorder may either recur or develop de novo. In the past, plasmapheresis was considered beneficial. More recently, the availability of eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, has become the treatment of choice, either as monotherapy or with plasma exchange. However, uncertainties remain regarding the optimal duration and dosing of long-term therapy, particularly in transplant recipients.
2026-09-01 | Abstract No: 516 Complement-Mediated Atypical Hemolytic Uremic Syndrome with ANCA Positivity: Diagnosis and Eculizumab Treatment
Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) driven by dysregulation of the alternative complement pathway. Its diagnosis may be challenging when overlapping immune or infectious features are present. Antineutrophil cytoplasmic antibody (ANCA) positivity may lead clinicians to consider ANCA-associated vasculitis (AAV), potentially delaying recognition of complement-mediated TMA. This report describes a patient with ANCA positivity who developed renal-limited complement-mediated aHUS and showed clinical improvement after eculizumab therapy.
other
2026-07-22 | Towards scalable production of recombinant EIT as a protective antigen against EHEC.
Cattle are the major reservoir and an important source of environmental dissemination of enterohemorrhagic E. coli (EHEC), a human pathogen responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. Preharvest vaccines are aimed to reduce bacterial carriage and consequently, the impact of this zoonosis. The chimeric antigen EIT has demonstrated to be protective against EHEC in murine models. In a recent study, we proposed a simple and cost-effective approach for a vaccine formulation for cattle, in which EIT was expressed and recovered from the periplasm of the laboratory strain E. coli BL21. As a proof-of-concept, the protective efficacy in mice as well as the induction of humoral immune responses in bovines were verified. In this work, we aimed to improve the production of the recombinant antigen EIT using E. coli fed-batch fermentations. An initial screening was conducted to select the medium that best sustained EIT expression using lactose for heterologous induction. M9 medium supplemented with yeast extract yielded the highest relative levels of EIT and was used for subsequent fermentation in a stirred-tank bioreactor. Thus, EIT concentration and volumetric productivity increased by approximately 600% compared to shake-flask cultivations, while EIT yield relative to biomass and specific productivity increased by approximately 130%. Following thermal permeabilization of cells for antigen recovery, the method yielded, overall, about 350 doses per L of fermented culture. The process was reproducible across three independent fermentations while retaining EIT antigenicity, as assessed by ELISA, and functionality, as it could induce antibodies that inhibited actin pedestal formation in in vitro infection assays. Thus, heterologous EIT expression was successfully transferred to a stirred-tank bioreactor, increasing antigen output and establishing a basis for further development of a scalable process for EHEC vaccine applications.
2026-05-27 | Treatment of Shiga toxin-producing E. coli infection by CRISPR-Cas-targeted cleavage of the Shiga toxin gene in animal models.
Escherichia coli is not only a ubiquitous gut commensal but also an opportunistic pathogen responsible for severe intestinal and extraintestinal infections. Shiga toxin-producing E. coli (STEC) poses a notable public health threat, particularly in children, where infections can lead to bloody diarrhea and progress to hemolytic uremic syndrome, a life-threatening condition with long-term complications. Antibiotics are contraindicated in STEC infections because of their potential to induce prophages carrying Shiga toxin (stx) genes, triggering toxin production. Here, we developed a CRISPR-based antimicrobial strategy using a Cas12 nuclease to selectively eliminate O157 STEC clinical isolates, cleaving more than 99% of stx variants, and prevent toxin release. To enable targeted delivery, we engineered a bacteriophage-derived capsid to specifically transfer a nonreplicative DNA payload to E. coli O157, preventing its dissemination. Our therapeutic candidate, EB003, reduced bacterial burden in a murine STEC colonization model. Moreover, EB003 mitigated clinical symptoms, abrogated Stx-mediated toxicity, and accelerated epithelial repair at therapeutically relevant doses in an infant rabbit disease model. These findings demonstrate the potential of CRISPR-based antimicrobials for treating STEC infections and support further clinical development of EB003 as a precision therapeutic against antibiotic-refractory bacterial pathogens.
2026-02-04 | Engineered bacterial therapy suppresses Enterohemorrhagic Escherichia coli through metabolic competition and virulence silencing.
Enterohemorrhagic Escherichia coli (EHEC) is a severe foodborne pathogen that can lead to hemolytic uremic syndrome. However, antibiotics are contraindicated for EHEC treatment due to toxin release and gut microbiota disruption. Here we report a dual‑mechanism therapeutic strategy combining an engineered Escherichia coli Nissle 1917 strain (EcN3) with 2'‑fucosyllactose (2‑FL) delivered via multicompartment microspheres (MCMs). EcN3 expresses α‑L‑fucosidase to hydrolyze 2‑FL into lactose and fucose. Lactose enhances glucuronic acid utilization, limiting a preferred nutrient of EHEC, whereas fucose activates FusKR signaling to suppress virulence gene expression. MCMs confer gastric protection and enable targeted colonic release, ensuring coordinated activity. In female mouse models and infant rabbit models of Citrobacter rodentium and EHEC infection, this system reduces intestinal colonization, virulence gene expression and epithelial damage without inducing Shiga toxin production. Moreover, MCMs-based strategy preserves the relative abundance of Lactobacillus, and promotes intestinal integrity. This targeted strategy presents a viable alternative to antibiotics, addressing EHEC pathogenesis and antibiotic resistance.
2026-01-16 | Treatment of atypical hemolytic uremic syndrome and C3 glomerulopathy in mice by hepatic expression of factor D.
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are diseases driven by dysregulation of the alternative pathway (AP) complement. Current treatments of these diseases involve the use of frequent and often large doses of monoclonal antibodies, peptide inhibitors, or chemical inhibitors of complement proteins, with various limitations. In this study, we describe ectopic expression of factor D (FD) in the liver as a potential novel therapy for these indications. Unlike most plasma complement proteins, which are synthesized in the liver, FD, a serine protease in the AP, is synthesized primarily in fat tissues. Newly synthesized FD is released largely as an inactive proenzyme that requires activation by mannose-binding lectin-associated serine protease 3 (MASP3) to form the mature enzyme. We found serendipitously that ectopic expression of mature FD, but not pro-FD, in the mouse liver led to C3-dependent depletion of plasma factor B (FB) and abolished AP complement activity. Coexpression of C3, FB, and mature FD in cultured Hepa1-6 cells caused intracellular FB activation and consumption, probably within the secretory vesicles where all 3 proteins may colocalize. Hepatic FD-mediated local FB activation and depletion effectively prevented disease development in murine models of aHUS and C3G. Our results suggest that segregated tissue production of FD, FB, and C3, as well as FD regulation by MASP3, is necessary to prevent in situ FB activation and depletion. Ectopic expression of mature FD in the liver is an effective way to inhibit FB expression and AP complement activity, with potential therapeutic applications in diseases such as aHUS and C3G.
2025-11-07 | Spatially and Multivalent Matched Neutralizing Aptamer-Based DNA Nanostructure Alleviates Shiga Toxin Type 2 Infection.
Shiga toxin type 2 (Stx2) is a risk factor for acute bloody diarrhea and hemolytic uremic syndrome, which has posed a major threat to global public health. Currently, there is a lack of effective strategies to combat Stx2 infection. Herein, according to the structural characteristics and infection mechanism of Stx2, we have designed a structure mediated by self-assembling DNA tetrahedral nanoframes (TDN), which can orderly assemble three neutral aptamers (TDN-S) to prevent Stx2 from entering cells and inhibit Stx2 infection. The neutralizing aptamers SA, SB, and SC can respectively bind to the three sites (sites 1, 2, and 3) on the Stx2 B subunit, which coincidentally occupy the binding sites of Stx2 and Gb3 receptor. Benefiting from the simultaneous capture of three active sites, spatial matching, and the steric hindrance effect, TDN-S exhibits excellent neutralization efficiency against Stx2. The inhibition ability of Stx2 infection in vitro was evaluated by cell viability, intracellular fluorescence imaging, and ROS levels, and the inhibition rate was as high as 80.44%. The TDN-S significantly reduces the damage to the liver, kidneys, and intestines and the inflammatory response in vivo. Overall, the neutralization strategy with multimodal interaction provides a new way to alleviate the Stx2 toxicity and serves as a model for other wide-range toxin-like inhibitions.
small molecules
2026-09-26 | Gypenosides Mitigate STEC-Induced Intestinal Injury Through Modulation of Ferroptosis Involving the ATF4-CHAC1-GPX4 Axis.
Shiga toxin-producing Escherichia coli (STEC) infection causes severe enteropathies and hemolytic uremic syndrome, yet non-antibiotic therapeutic strategies remain limited. This study evaluated whether gypenosides (GPs) protect against STEC-induced intestinal injury and investigated the underlying mechanisms. Mice were pretreated with GPs prior to STEC challenge, and protective effects were comprehensively assessed through survival analysis, bacterial burden quantification, transcriptomic profiling, flow cytometry, electron microscopy, and Western blotting. GPs significantly improved survival rates, alleviated diarrheal symptoms, reduced bacterial dissemination in systemic organs, and lowered Stx2 toxin levels. Furthermore, GPs effectively restored gut microbiota dysbiosis by enriching beneficial bacterial genera. Transcriptomic analysis suggested that GP treatment was associated with suppression of ferroptosis-related signaling pathways. Ultrastructural examination demonstrated ameliorated mitochondrial vacuolization, and biochemical assays confirmed decreased Fe2+ accumulation and attenuated lipid peroxidation. Mechanistically, these changes were associated with modulation of the ATF4-CHAC1-GPX4 axis and suppression of ferroptosis, together with preservation of mitochondrial integrity. Collectively, these findings identify GPs as a promising protective candidate against STEC-induced intestinal injury and highlight the ATF4-CHAC1-GPX4 axis as a candidate pathway for further mechanistic investigation.
2026-09-25 | Complement diagnostics and therapeutics for the pediatric population: early successes and opportunities for further advancement.
Complement-mediated diseases are individually rare, often rapidly progressive, and historically associated with high rates of permanent organ injury or death but are now among the most therapeutically actionable conditions in pediatric nephrology, hematology, and rheumatology. As demonstrated by thrombotic microangiopathy, and hemolytic uremic syndrome in particular, diagnostic delay can contribute directly to irreversible kidney injury. Complement inhibition has substantially improved outcomes in these conditions that previously carried a substantial risk of end-stage kidney disease. This review addresses the complement system as a clinical and therapeutic framework for the practicing pediatric clinician. The pathophysiology of the major complement-mediated diseases affecting children is examined, with atypical hemolytic uremic syndrome and transplant-associated thrombotic microangiopathy as central disease models alongside paroxysmal nocturnal hemoglobinuria, C3 glomerulopathy, IgA nephropathy, and ANCA-associated vasculitis. Approved complement inhibitors are reviewed by mechanistic position in the cascade, with attention to the clinical implications of terminal versus proximal pathway inhibition. Laboratory diagnosis, monitoring, and assessment of complement blockade adequacy are addressed, including practical limitations of complement testing in clinical practice. Critical gaps are examined, including diagnostic delays, absent validated biomarkers, inadequate pediatric trial infrastructure, and conditions without targeted therapies. Emerging therapeutics, point-of-care diagnostics, and pediatric-specific considerations including transition of care and reproductive counseling complete the review. Complement therapeutics have meaningfully altered the trajectory of some of the most severe and inadequately treated pediatric diseases. This field continues to evolve rapidly, with expanding indications and novel agents, though drug development challenges, diagnostic and monitoring gaps, and equitable consideration of pediatric application of these novel agents remain essential priorities.
2026-09-13 | The antibiotic NAB815 does not induce SOS response and toxin production in Shiga toxin-producing Escherichia coli at sub-bactericidal concentrations.
Hemolytic uremic syndrome (HUS) is a rare but severe clinical condition, primarily caused by Shiga toxin-producing Escherichia coli (STEC) infections. A critical early step in the pathogenesis of HUS is the entry of Shiga toxins (Stx) into the bloodstream, where they interact with circulating blood cells via globotriaosylceramide (Gb3Cer) and Toll-like receptor 4 (TLR4). This triggers the release of Stx-containing extracellular vesicles (EV), a critical late step for HUS onset. Currently, there are no specific therapeutic interventions for HUS, and the management of STEC-infected patients is largely supportive. Antibiotics are generally avoided due to the risk of inducing the bacterial SOS response thereby enhancing Stx phage activation and toxin production. Recently, our group developed NAB815, a polymyxin B derivative capable of inhibiting Stx2a binding to TLR4, thereby reducing the release of Stx-containing EV and enhancing survival in cellular and animal models. However, as NAB815 is an antibiotic, it is unclear whether it might also have an undesirable impact on Stx production via phage activation. Here, we demonstrate that exposure of reporter or wild type clinical STEC strains to NAB815 neither triggered the SOS response nor increased Stx1 or Stx2 amounts. These results indicate that NAB815 may mitigate Stx-mediated toxicity without having an off-target effect on Stx phage activation, supporting its potential as a safe therapeutic intervention for STEC patients.
2026-09-11 | Complement in Kidney Disease: Core Curriculum 2026.
The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.
2026-08-26 | Recurrent Postpartum Atypical Hemolytic Uremic Syndrome Caused by a C3 Pathogenic Variant: A Case Report.
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy (TMA) driven by uncontrolled activation of the complement alternative pathway. Pregnancy and postpartum period are well-recognized triggers for aHUS. In recent years, the prognosis of aHUS has substantially improved with the use of complement-targeted therapies. However, timely recognition, accurate classification, and prompt treatment initiation remain critical. This report describes a case of postpartum aHUS caused by a C3 gene mutation that achieved complete clinical and laboratory remission following a treatment strategy that included early eculizumab, plasma infusion, and renal replacement therapy. Drawing on the literature, we discuss key diagnostic and therapeutic considerations as well as clinical implications to provide guidance for clinical practice. We present a 35-year-old multiparous woman (gravida 3, para 3) who developed acute kidney injury, microangiopathic hemolytic anemia, and severe thrombocytopenia 2 days after cesarean section. She had a history of similar TMA episode 8 years postpartum. Laboratory investigations showed normal ADAMTS13 activity, negative autoimmune antibodies, reduced serum complement C3 and factor I levels, and elevated sC5b-9. Whole-exome sequencing identified a heterozygous pathogenic mutation in the C3 gene: c.1774C>T (p.R592W). Eculizumab was initiated within 24 hours of clinical suspicion, combined with plasma infusion and renal replacement therapy. The patient achieved complete clinical and laboratory remission: renal function, platelet count, hemoglobin, and lactate dehydrogenase returned to normal within 4 weeks. She remained stable during long-term follow-up on maintenance eculizumab. This case is particularly instructive because the patient had a prior TMA episode that was retrospectively suggestive of aHUS following genetic confirmation; however, definitive reclassification could not be established with certainty due to the lack of genetic testing at that time. This case highlights that C3 variant-mediated aHUS can be repeatedly triggered by pregnancy. Early recognition, prompt initiation of C5 inhibition, and multidisciplinary care are critical for renal recovery and favorable outcomes. Clinicians should distinguish postpartum aHUS from preeclampsia, HELLP syndrome, and TTP to prevent treatment delay.
cell therapies
2026-09-01 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center.
Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-08-31 | Pathogenesis and therapeutic strategies in the interaction between gut microbiota and enterohemorrhagic Escherichia coli infection.
Enterohemorrhagic Escherichia coli (EHEC) is a major foodborne pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. Increasing evidence indicates that the gut microbiota plays a central role in modulating EHEC pathogenesis through complex metabolic and signaling networks. Beneficial commensals, including Bifidobacterium, Lactobacillus, and segmented filamentous bacteria, contribute to colonization resistance by competing for nutrients and adhesion sites, producing antimicrobial metabolites, and enhancing epithelial barrier integrity. In contrast, certain species such as Bacteroides thetaiotaomicron and Enterococcus faecalis may promote EHEC virulence by altering intestinal nutrient availability or triggering the expression of virulence genes. Microbiota-derived metabolites, including short-chain fatty acids, succinate, indole, riboflavin, nicotinamide, ethanolamine, and L-malate, act as important regulatory signals that connect microbial metabolism with LEE-mediated virulence pathways. Understanding these host-microbe-pathogen interactions provides a mechanistic basis for developing microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation that enhance colonization resistance and attenuate virulence. Integration of AI-based analytics with multi-omics approaches is expected to facilitate the design of personalized, mechanism-driven therapeutic strategies for the control of EHEC infection.
2026-08-19 | Surface Functionalization of Small Extracellular Vesicles Derived from Caco-2 and HEK293T Cells in the Neutralization of Shiga Toxin 1 Subunit B.
Shiga toxins (Stx) are key virulence factors of Shiga toxin-producing Escherichia coli (STEC), which are responsible for severe foodborne infections that can progress to hemolytic-uremic syndrome (HUS). Currently, no specific antitoxin therapies are available. In this study, we devised a glycoengineering strategy utilizing Functional-Spacer-Lipid (FSL) conjugates to create small extracellular vesicles (sEVs)-based decoy receptors for Shiga toxin type 1 (Stx1). sEVs isolated from human Caco-2 and HEK293T cells were functionalized with Gb3 trisaccharide (Galα1→4Galβ1→4Glc)-containing FSL conjugates, yielding Gb3-decorated vesicles displaying the Galα1→4Gal epitope. Characterization of FSL-modified sEVs confirmed that FSL incorporation did not adversely affect sEV morphology, size distribution, or surface charge. Western blotting and bead-assisted flow cytometry verified the presence of exosomal markers (CD9 and CD63) and the Gb3 epitope on modified vesicles. Gb3-tagged sEVs from both cell types exhibited high specificity in binding Stx1B, while control vesicles carrying Galili epitope (Galα1→3Galβ1→4GlcNAc), lacking Stx1B binding, demonstrated negligible binding. Gb3-expressing Caco-2 cell-based assays revealed that Gb3-decorated sEVs markedly reduced Stx1B binding to Caco-2 cells, indicating effective competition with cellular receptors. Furthermore, glycoengineered sEVs did not impair Caco-2 cell viability at concentrations sufficient for Stx1B sequestration. These findings establish FSL-mediated glycoengineering as a rapid and versatile approach for generating sEV-based decoy receptors that effectively bind Stx1B. Gb3-containing human sEVs may serve as an agent for neutralizing Stx1B and potentially other glycan-binding toxins, supporting the development of promising next-generation antitoxin therapeutics.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2024-11-18 | Gb3 trisaccharide-bearing exosomes as a novel neutralizer for Shiga toxin type 1.
Shiga toxin types 1 (Stx1) and 2 (Stx2), produced by Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae, are key virulence factors responsible for severe foodborne diseases, such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). The receptors for Stxs are Gb3 and P1 glycotope, which contain the Galα1→4Gal epitope and are synthesized by human α1,4-galactosyltransferase (A4galt). Stx-related infections pose a global public health challenge, owing to the limited therapeutic options due to the restricted use of antibiotics. Therefore, there is an urgent need to develop novel therapeutic strategies. This study proposes an innovative strategy utilizing exosomes derived from CHO-Lec2 cells, which were modified with Functional-Spacer-Lipid (FSL) conjugates bearing the Gb3 carbohydrate epitope (exo-Gb3-FSL). Flow cytometry analysis confirmed the presence of Galα1→4Gal disaccharides on exo-Gb3-FSL constructs, enabling them to bind Stx1. Moreover, using CHO-Lec2 cells evaluated the ability of exo-Gb3-FSL agents to bind Stx1 and protect these cells from Stx1-mediated cytotoxicity. For Stx1-treated CHO-Lec2 cells, increased cell survival was observed when using 25 μM exo-Gb3-FSL constructs, compared to control cells. These findings highlight the potential of exosome-based anti-Stx1 agents as promising alternatives to conventional therapies. This innovative strategy may provide novel directions for studies on Stx1 neutralization, offering a valuable strategy for the treatment of Stx-related diseases.
proteins
2026-08-26 | Inhibitory Effects of Oxysterlina 3, Satanin 1, and Curvicin Cecropins on the Growth and stx2 Gene Expression of Shiga Toxin-Producing Escherichia coli (STEC).
Shiga toxin-producing Escherichia coli (STEC) poses a significant health risk, with Stx1 and Stx2 as key virulence factors associated with hemolytic uremic syndrome (HUS). Current STEC treatment relies on supportive care, avoiding antimicrobial therapy. This study evaluates the antibacterial activity of three cecropin peptides and their effect on the expression of the stx2 gene in STEC. Employing microdilution assays and RT-qPCR, all three cecropins demonstrated antibacterial efficacy, displaying MIC and MBC values of 12.5 µg/mL, and decreased gene expression levels following treatment. Notably, these cecropins not only inhibited STEC growth but also significantly reduced stx2 mRNA expression. These findings underscore the therapeutic potential of cecropins as an alternative treatment for STEC infections and suggest they may mitigate associated complications.
2026-05-05 | Targeting StxB-mediated intracellular trafficking as a pharmacological strategy for anti-virulence intervention.
Shiga toxin (Stx) is a prototypical bacterial toxin responsible for severe diseases such as hemorrhagic colitis and hemolytic uremic syndrome (HUS). Despite extensive research efforts, therapeutic options remain limited, and no approved strategy directly targets its pathogenic mechanism. Shiga toxin belongs to the AB5 family and consists of a catalytically active A subunit (StxA) and a pentameric B subunit (StxB). Importantly, its pathogenicity depends not simply on the enzymatic activity of StxA but critically on the host cell entry and intracellular trafficking mediated by the StxB. Through multivalent binding to the Gb3 receptor, StxB reorganizes membrane microdomains and initiates endocytosis. A substantial fraction of internalized toxin escapes lysosomal degradation and instead exploits the Golgi-endoplasmic reticulum (ER) retrograde transport pathway to enable cytosolic delivery of StxA. This sequence of events constitutes a rate-limiting determinant of toxin pathogenicity and demonstrates that StxB actively orchestrates host intracellular trafficking networks rather than serving merely as a receptor-binding component. In this review, we integrate molecular and biophysical mechanisms of StxB-mediated intracellular trafficking and comparatively evaluate the druggability of each trafficking step. In particular, we reinterpret approaches such as inhibition of toxin binding, disruption of membrane microdomains, blockade of endocytosis, and inhibition of Golgi-ER retrograde transport from the perspective of anti-virulence therapy. We propose that selective modulation of StxB-dependent trafficking bottlenecks represents a conceptually novel therapeutic strategy that can attenuate host damage while reducing the risk of resistance development.
2025-10-05 | Structural characterization of Factor H via computational methods: Implications for disease and therapy.
Complement Factor H (CFH) is a crucial regulator of the alternative complement pathway, maintaining immune balance by preventing excessive activation that damages host tissues. This liver-derived glycoprotein binds to C3b and inhibits C3 convertase formation, with its N-terminal (CCP1-4) and C-terminal (CCP19-20) domains playing key roles in complement regulation and host recognition. In this in silico study, we explored the molecular architecture and interaction landscape of Factor H, identifying highly conserved motifs-particularly in CCP4, CCP8-9, and CCP12, as well as conserved lysine residues across CCP1-4. Motifs 11, 14, and 18 were mapped to the C-terminal domains (CCP18-20). Ligand interaction analysis revealed that heparin binds to CCP2 and CCP15, malondialdehyde binds to CCP3, N-glycoloyl-D-glucosamine to CCP11, and O-sialic acid to CCP11 and CCP12. Additionally, FH was shown to interact with endogenous ligands, including PTX3, fibromodulin, osteoadherin, chondroadherin, prion protein, adrenomedullin, and annexin II. These findings provide deeper insight into FH's role in complement-related disorders, such as aHUS, AMD, and dense deposit disease, supporting its potential as a therapeutic target for precision immune modulation.
2025-05-13 | The 4 functional segments of Factor H: Role in physiological target recognition and contribution to disease.
Factor H controls proximal complement activation, and its dysfunction leads to diseases that often manifest in the kidney. Structural and functional analyses have identified 4 distinct functional segments: an N-terminal regulatory unit, a cell binding unit, a segment with combined low-affinity C3b and heparin sites, and a C-terminal recognition or sensor unit with overlapping C3b/C3d and heparin sites. Three segments are linked to diseases. The regulatory segment is affected in C3 glomerulopathy and antineutrophil cytoplasmic antibody-associated vasculitis. The second segment includes the Y402H polymorphism of age-related macular degeneration, is associated with different types of cancer, and is targeted by pathogens. The C-terminal sensor segment is involved in atypical hemolytic uremic syndrome, in FHR1:FHR3 deficient and autoantibody-positive hemolytic uremic syndrome form and is exploited by pathogens. Factor H function is modulated by Factor H like protein 1 and FHR1, 2 plasma proteins that share segments with Factor H. This interplay is critical for fine-tuning local complement. Understanding Factor H's physiological role, as well as the impact of its absence, mutations, or autoantibody targeting, provides insights into disease mechanisms and provides opportunities for therapeutic intervention by using full-length Factor H, its fragments, or complement-modulatory compounds.
2025-01-12 | A mutant complement factor H (W1183R) enhances proteolytic cleavage of von Willebrand factor by ADAMTS-13 under shear.
A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood. To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution. We employed recombinant protein expression, purification, and various biochemical and biophysical tools. Purified recombinant W1183R-CFH but not wild-type (WT) CFH protein enhanced the proteolytic cleavage of both peptidyl and multimeric VWF substrates by recombinant ADAMTS-13 in a concentration-dependent manner. Microscale thermophoresis assay demonstrated that both W1183R-CFH and WT-CFH proteins bound various VWF fragments (eg, AIM-A1, A1-A2-A3, D'D3, D'D3-A1, and D'D3-A1-A2) with high affinities. Optical tweezer experiments further showed a concentration-dependent alteration in the contour length (Lc) and the persistent length (Lp) following pulling VWF-A2 domain in the presence of W1183R-CFH or WT-CFH protein. AlphaFold experiments revealed conformational changes in the VWF-A2, particularly the central region where the cleavage bond resides following addition of W1183R-CFH or WT-CFH protein. These results demonstrate for the first time that W1183R-CFH but not WT-CFH protein enhances the proteolytic cleavage of VWF by ADAMTS-13 under shear. This may be achieved by mechanic-induced conformational changes of the central A2 domain, leading to an enhanced cleavage of Tyr1605-Met1606 bond by ADAMTS-13 under pathophysiological conditions.
antibodies
2026-09-26 | TLR4: A Potential Therapeutic Target in the Experimental Pathogenesis of Hemolytic-Uremic Syndrome.
Childhood infections by Shiga toxin (Stx)-producing Escherichia coli (STEC) cause bloody diarrhea and the life-threatening hemolytic-uremic syndrome (HUS). Stx2, produced by STEC in the gut, is released into the bloodstream and interacts with circulating cells (monocytes, neutrophils, and platelets) through two different receptors: Gb3Cer (globotriaosylceramide) and Toll-like receptor 4 (TLR4). Consequently, blood cells form leukocyte/platelet aggregates and release pathogenic Stx2-containing extracellular vesicles (EVs) that, by damaging the kidney, induce the transition from bloody diarrhea to HUS. Human blood was incubated with Stx2 to induce the formation of neutrophil/platelet and platelet-only aggregates (observed in May-Grünwald Giemsa-stained blood smears) and pathogenic blood cell-derived EVs (isolated by size-exclusion chromatography or differential centrifugation) toxic to Vero cells (assessed by a viability assay). In the presence of a monoclonal antibody against TLR4 (anti-TLR4), the formation of neutrophil/platelet and platelet-only aggregates was greatly reduced compared to treatment with Stx2 alone. Moreover, anti-TLR4 significantly decreased the total mass of pathogenic blood cell-derived EVs produced by Stx2 (detected by nanoparticle tracking analysis), which proved less toxic to Vero cells than those produced by Stx2 alone. The impairment of the Stx2-TLR4 axis obtained during the experimental pathogenesis of HUS provides proof-of-concept evidence supporting TLR4 as a potential therapeutic target.
2026-09-25 | Atypical Hemolytic Uremic Syndrome in a Patient With Inflammatory Bowel Disease
Atypical hemolytic uremic syndrome is a life-threatening thrombotic microangiopathy due to complement dysregulation that can be triggered by systemic inflammatory states. We describe a patient with inflammatory bowel disease presenting with pain, melena, and laboratory test results showing hemolytic anemia, thrombocytopenia, and acute kidney injury. Subsequent testing led to a diagnosis of atypical hemolytic uremic syndrome, prompting initiation of eculizumab with rapid improvement in his hemolysis, thrombocytopenia, and acute kidney injury. Providers should maintain a high index of suspicion for uncommon but grave conditions associated with inflammatory bowel disease and consider complement testing if thrombotic microangiopathy is suspected.
2026-09-23 | Atypical Hemolytic Uremic (Ahus) Syndrome with Kidney Injury in Pediatric Patient: A Case Report
Hemolytic uremic syndrome is a form of thrombotic microangiopathy (TMA) which is characterized by thrombocytopenia, microangiopathy hemolytic anemia and renal impairment. Approximately 10% of cases of the hemolytic–uremic syndrome is classified as atypical, since they are not caused by either Stx-producing bacteria or streptococci. Early recognition and initiation of appropriate treatment are essential in patient with a HUS which involves supportive care and inhibition of complement system. Plasmatherapy is recommended as first line treatment approach for aHUS. Timely initiation of plasma exchange, dialysis along with supportive treatment results in gradual improvement in 60- 70% of cases. There are other evolving approaches for the management of a HUS which shows promising results such as anti-C5 monoclonal antibody such as eculizumab, and treating complementary etiology
2026-09-15 | Atypical hemolytic uremic syndrome in kidney transplantation.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder that affects individuals of any age. It is caused by genetic abnormalities of the alternative complement pathway, arising from inherited or de novo mutations, or from acquired factors such as autoantibodies against complement proteins, including complement factor H. Clinically, aHUS is characterized by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. However, its clinical presentation may be difficult to distinguish from typical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. aHUS is driven by uncontrolled activation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis. Atypical HUS may also occur after kidney transplantation, either as recurrence of the native disease or as de novo post-transplant thrombotic microangiopathy. The diagnosis of post-transplant aHUS relies on the presence of the above-mentioned classic triad and the exclusion of secondary causes such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS. The pathophysiology is similar, involving either genetic mutations affecting complement proteins or acquired dysregulation due to autoantibodies. Historically, plasma exchange was used to replace dysfunctional complement regulators and remove circulating autoantibodies, with variable success. After transplantation, the disorder may either recur or develop de novo. In the past, plasmapheresis was considered beneficial. More recently, the availability of eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, has become the treatment of choice, either as monotherapy or with plasma exchange. However, uncertainties remain regarding the optimal duration and dosing of long-term therapy, particularly in transplant recipients.
2026-09-01 | Abstract No: 516 Complement-Mediated Atypical Hemolytic Uremic Syndrome with ANCA Positivity: Diagnosis and Eculizumab Treatment
Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) driven by dysregulation of the alternative complement pathway. Its diagnosis may be challenging when overlapping immune or infectious features are present. Antineutrophil cytoplasmic antibody (ANCA) positivity may lead clinicians to consider ANCA-associated vasculitis (AAV), potentially delaying recognition of complement-mediated TMA. This report describes a patient with ANCA positivity who developed renal-limited complement-mediated aHUS and showed clinical improvement after eculizumab therapy.
other
2026-07-22 | Towards scalable production of recombinant EIT as a protective antigen against EHEC.
Cattle are the major reservoir and an important source of environmental dissemination of enterohemorrhagic E. coli (EHEC), a human pathogen responsible for outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) worldwide. Preharvest vaccines are aimed to reduce bacterial carriage and consequently, the impact of this zoonosis. The chimeric antigen EIT has demonstrated to be protective against EHEC in murine models. In a recent study, we proposed a simple and cost-effective approach for a vaccine formulation for cattle, in which EIT was expressed and recovered from the periplasm of the laboratory strain E. coli BL21. As a proof-of-concept, the protective efficacy in mice as well as the induction of humoral immune responses in bovines were verified. In this work, we aimed to improve the production of the recombinant antigen EIT using E. coli fed-batch fermentations. An initial screening was conducted to select the medium that best sustained EIT expression using lactose for heterologous induction. M9 medium supplemented with yeast extract yielded the highest relative levels of EIT and was used for subsequent fermentation in a stirred-tank bioreactor. Thus, EIT concentration and volumetric productivity increased by approximately 600% compared to shake-flask cultivations, while EIT yield relative to biomass and specific productivity increased by approximately 130%. Following thermal permeabilization of cells for antigen recovery, the method yielded, overall, about 350 doses per L of fermented culture. The process was reproducible across three independent fermentations while retaining EIT antigenicity, as assessed by ELISA, and functionality, as it could induce antibodies that inhibited actin pedestal formation in in vitro infection assays. Thus, heterologous EIT expression was successfully transferred to a stirred-tank bioreactor, increasing antigen output and establishing a basis for further development of a scalable process for EHEC vaccine applications.
2026-05-27 | Treatment of Shiga toxin-producing E. coli infection by CRISPR-Cas-targeted cleavage of the Shiga toxin gene in animal models.
Escherichia coli is not only a ubiquitous gut commensal but also an opportunistic pathogen responsible for severe intestinal and extraintestinal infections. Shiga toxin-producing E. coli (STEC) poses a notable public health threat, particularly in children, where infections can lead to bloody diarrhea and progress to hemolytic uremic syndrome, a life-threatening condition with long-term complications. Antibiotics are contraindicated in STEC infections because of their potential to induce prophages carrying Shiga toxin (stx) genes, triggering toxin production. Here, we developed a CRISPR-based antimicrobial strategy using a Cas12 nuclease to selectively eliminate O157 STEC clinical isolates, cleaving more than 99% of stx variants, and prevent toxin release. To enable targeted delivery, we engineered a bacteriophage-derived capsid to specifically transfer a nonreplicative DNA payload to E. coli O157, preventing its dissemination. Our therapeutic candidate, EB003, reduced bacterial burden in a murine STEC colonization model. Moreover, EB003 mitigated clinical symptoms, abrogated Stx-mediated toxicity, and accelerated epithelial repair at therapeutically relevant doses in an infant rabbit disease model. These findings demonstrate the potential of CRISPR-based antimicrobials for treating STEC infections and support further clinical development of EB003 as a precision therapeutic against antibiotic-refractory bacterial pathogens.
2026-02-04 | Engineered bacterial therapy suppresses Enterohemorrhagic Escherichia coli through metabolic competition and virulence silencing.
Enterohemorrhagic Escherichia coli (EHEC) is a severe foodborne pathogen that can lead to hemolytic uremic syndrome. However, antibiotics are contraindicated for EHEC treatment due to toxin release and gut microbiota disruption. Here we report a dual‑mechanism therapeutic strategy combining an engineered Escherichia coli Nissle 1917 strain (EcN3) with 2'‑fucosyllactose (2‑FL) delivered via multicompartment microspheres (MCMs). EcN3 expresses α‑L‑fucosidase to hydrolyze 2‑FL into lactose and fucose. Lactose enhances glucuronic acid utilization, limiting a preferred nutrient of EHEC, whereas fucose activates FusKR signaling to suppress virulence gene expression. MCMs confer gastric protection and enable targeted colonic release, ensuring coordinated activity. In female mouse models and infant rabbit models of Citrobacter rodentium and EHEC infection, this system reduces intestinal colonization, virulence gene expression and epithelial damage without inducing Shiga toxin production. Moreover, MCMs-based strategy preserves the relative abundance of Lactobacillus, and promotes intestinal integrity. This targeted strategy presents a viable alternative to antibiotics, addressing EHEC pathogenesis and antibiotic resistance.
2026-01-16 | Treatment of atypical hemolytic uremic syndrome and C3 glomerulopathy in mice by hepatic expression of factor D.
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are diseases driven by dysregulation of the alternative pathway (AP) complement. Current treatments of these diseases involve the use of frequent and often large doses of monoclonal antibodies, peptide inhibitors, or chemical inhibitors of complement proteins, with various limitations. In this study, we describe ectopic expression of factor D (FD) in the liver as a potential novel therapy for these indications. Unlike most plasma complement proteins, which are synthesized in the liver, FD, a serine protease in the AP, is synthesized primarily in fat tissues. Newly synthesized FD is released largely as an inactive proenzyme that requires activation by mannose-binding lectin-associated serine protease 3 (MASP3) to form the mature enzyme. We found serendipitously that ectopic expression of mature FD, but not pro-FD, in the mouse liver led to C3-dependent depletion of plasma factor B (FB) and abolished AP complement activity. Coexpression of C3, FB, and mature FD in cultured Hepa1-6 cells caused intracellular FB activation and consumption, probably within the secretory vesicles where all 3 proteins may colocalize. Hepatic FD-mediated local FB activation and depletion effectively prevented disease development in murine models of aHUS and C3G. Our results suggest that segregated tissue production of FD, FB, and C3, as well as FD regulation by MASP3, is necessary to prevent in situ FB activation and depletion. Ectopic expression of mature FD in the liver is an effective way to inhibit FB expression and AP complement activity, with potential therapeutic applications in diseases such as aHUS and C3G.
2025-11-07 | Spatially and Multivalent Matched Neutralizing Aptamer-Based DNA Nanostructure Alleviates Shiga Toxin Type 2 Infection.
Shiga toxin type 2 (Stx2) is a risk factor for acute bloody diarrhea and hemolytic uremic syndrome, which has posed a major threat to global public health. Currently, there is a lack of effective strategies to combat Stx2 infection. Herein, according to the structural characteristics and infection mechanism of Stx2, we have designed a structure mediated by self-assembling DNA tetrahedral nanoframes (TDN), which can orderly assemble three neutral aptamers (TDN-S) to prevent Stx2 from entering cells and inhibit Stx2 infection. The neutralizing aptamers SA, SB, and SC can respectively bind to the three sites (sites 1, 2, and 3) on the Stx2 B subunit, which coincidentally occupy the binding sites of Stx2 and Gb3 receptor. Benefiting from the simultaneous capture of three active sites, spatial matching, and the steric hindrance effect, TDN-S exhibits excellent neutralization efficiency against Stx2. The inhibition ability of Stx2 infection in vitro was evaluated by cell viability, intracellular fluorescence imaging, and ROS levels, and the inhibition rate was as high as 80.44%. The TDN-S significantly reduces the damage to the liver, kidneys, and intestines and the inflammatory response in vivo. Overall, the neutralization strategy with multimodal interaction provides a new way to alleviate the Stx2 toxicity and serves as a model for other wide-range toxin-like inhibitions.
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Drug Discovery Landscape
2 orphan drug designations for Hemolytic uremic syndrome.
2 orphan drug designations for Hemolytic uremic syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Protein-based delivery vector carrying a DNA payload encoding an RNA-guided nuclease that targets stx genes of Shiga toxin-producing Escherichia coli | gene editing enzymes | EMA | — | Eligo Bioscience |
Equine immunoglobulin F(ab')2 fragments targeting Shiga toxin | antibodies | EMA | Chemo Research S.L. |
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