Complement Activation-Independent Attenuation of SARS-CoV-2 Infection by C1q and C4b-Binding Protein

Viruses, Journal Year: 2023, Volume and Issue: 15(6), P. 1269 - 1269

Published: May 29, 2023

The complement system is a key component of the innate immune response to viruses and proinflammatory events. Exaggerated activation has been attributed induction cytokine storm in severe SARS-CoV-2 infection. However, there also an argument for protective role proteins, given their local synthesis or at site viral This study investigated activation-independent C1q C4b-binding protein (C4BP) against interactions C1q, its recombinant globular heads, C4BP with spike receptor binding domain (RBD) were examined using direct ELISA. In addition, RT-qPCR was used evaluate modulatory effect these proteins on SARS-CoV-2-mediated response. Cell luciferase-based entry assays utilised assess effects cell entry. bound directly pseudotype particles via RBD protein. heads found reduce as well transduction expressing lentiviral pseudotypes into transfected A549 cells human ACE2 TMPRSS2. Furthermore, treatment spike, envelope, nucleoprotein, membrane alphaviral triggered reduction mRNA levels cytokines chemokines such IL-1β, IL-8, IL-6, TNF-α, IFN-α, RANTES (as NF-κB) reduced infection-mediated NF-κB are synthesised primarily by hepatocytes; however, they produced macrophages, alveolar type II cells, respectively, locally pulmonary site. These findings support notion that can be infection manner, offering resistance inhibiting virus target host attenuating infection-associated inflammatory

Language: Английский

---

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(710)

Published: Aug. 23, 2023

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of mechanisms driving disease pathology. The complement system is not only a crucial component innate host defense but can also contribute to tissue injury. Although all pathways have been implicated pathogenesis, upstream drivers and downstream effects on injury remain poorly defined. We demonstrate that activation primarily mediated by alternative pathway, we provide comprehensive atlas alterations around time respiratory deterioration. Proteomic single-cell sequencing mapping across cell types tissues reveals division labor between lung epithelial, stromal, myeloid cells production, addition liver-derived factors. identify IL-6 STAT1/3 signaling as an driver responses, linking dysregulation approved therapies. Furthermore, exploratory proteomic study indicates inhibition C5 decreases epithelial damage markers severity. Collectively, these results support key druggable feature COVID-19.

Language: Английский

---

Complement is primarily activated in the lung in a mouse model of severe COVID-19

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111930 - 111930

Published: Feb. 1, 2025

In vitro studies and observational human disease data suggest the complement system contributes to SARS-CoV-2 pathogenesis, although how dysregulation develops in severe COVID-19 is unknown. Here, using a mouse-adapted virus (SARS2-N501YMA30) mouse model of COVID-19, we identify significant serologic pulmonary activation post-infection. We observed C3 airway alveolar epithelia, vascular endothelia. Our evidence suggests alternative pathway primary route activation, however, components both classical pathways are produced locally by respiratory epithelial cells following infection, increased cultures epithelia cytokine exposure. This tissue-specific response appears precede lung injury inflammation. results that defining feature mice, agreeing with previous publications, provide basis for further investigation into role COVID-19.

Language: Английский

---

Differences in biomarker levels and proteomic survival prediction across two COVID-19 cohorts with distinct treatments

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112046 - 112046

Published: Feb. 18, 2025

Language: Английский

---

Expanded Spectrum and Increased Incidence of Adverse Events Linked to COVID-19 Genetic Vaccines: New Concepts on Prophylactic Immuno-Gene Therapy, Iatrogenic Orphan Disease, and Platform-Inherent Challenges

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 450 - 450

Published: March 31, 2025

The mRNA- and DNA-based “genetic” COVID-19 vaccines can induce a broad range of adverse events (AEs), with statistics showing significant variation depending on the timing data analysis methods used. Focusing only lipid nanoparticle-enclosed mRNA (mRNA-LNP) vaccines, this review traces evolution statistical conclusions prevalence AEs incidents associated these from initial underestimation atypical, severe toxicities to recent claims suggesting possible contribution vaccinations excess deaths observed in many countries over past few years. Among hundreds different listed Pfizer’s pharmacovigilance survey, present categorizes main symptoms according organ systems, nearly all them being affected. Using US Vaccine Adverse Event Reporting System global vaccination dataset, comparison incidence rates induced by genetic versus flu revealed an average 26-fold increase use vaccines. difference is especially pronounced case ‘Brighton-listed’ AEs, which are also post-COVID conditions. these, increases relative given as x-fold rises, were 1152x, 455x, 226x, 218x, 162x, 152x, 131x for myocarditis, thrombosis, death, myocardial infarction, tachycardia, dyspnea, hypertension, respectively. delineates concept that be regarded prophylactic immuno-gene therapies chronic disabling might categorized iatrogenic orphan diseases. It examines unique vaccine characteristics could causally related abnormal immune responses potentially lead complications. These new insights may contribute improving safety platform technology assessing risk/benefit balance various products.

Language: Английский

---

Clinical C3 Inhibition With AMY‐101 Reveals Novel Insights Into IL‐8‐Driven Inflammation in COVID‐19

Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Language: Английский

---

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 28, 2023

ABSTRACT Background Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is hallmark COVID-19 but has not been investigated as potential determinant long COVID. Methods We quantified series complement proteins, including markers activation regulation, in plasma samples healthy convalescent confirmed history SARS-CoV-2 age/ethnicity/gender/infection/vaccine-matched patients Findings Markers classical (C1s-C1INH complex), alternative (Ba, iC3b), terminal pathway (C5a, TCC) were significantly elevated These combination had receiver operating characteristic predictive power 0.794. Other proteins regulators also quantitatively different between Generalized linear modeling further revealed clinically tractable just four these markers, namely the fragments iC3b, TCC, Ba, C5a, 0.785. Conclusions findings suggest biomarkers could facilitate currently available inhibitors be used to treat Funding This work was funded by National Institute for Health Research (COV-LT2-0041), PolyBio Foundation, UK Dementia Institute.

Language: Английский

---

De-stabilizing innate immunity in COVID-19: effects of its own positive feedback and erratic viraemia on the alternative pathway of complement

Royal Society Open Science, Journal Year: 2024, Volume and Issue: 11(1)

Published: Jan. 1, 2024

Complement provides powerful, fast responses in the human circulation to SARS-CoV-2 (COVID-19 virus) infection of lower respiratory tract. COVID-19 effects were investigated a revised silico Mass Action model complement's alternative pathway (AP) responses. Bursts newly circulating virions increased fission protein C3 into C3a and C3b via stimulation lectin or inhibited complement factor H. Viral reproduction sub-models incorporated smoothly exponential step-wise growth. Starting concentrations drawn randomly from published normal male female ranges each run for 10 days. B (FB) syntheses driven by Lectin Pathway led declining plasma increasing FB concentrations. The C3-convertase concentration, driver viral elimination, could match growth over three orders magnitude but near-complete exhaustion was more prevalent with than ‘smooth’ increases stimulation. be prolonged. Type 2 Diabetes hypertension greatly peak concentrations, as did short-term variability viraemia, pulmonary capillary clotting secondary acidosis. Positive feedback AP extends its response range at expense stability.

Language: Английский

---

Serum proteomics for the identification of biomarkers to flag predilection of COVID19 patients to various organ morbidities

Clinical Proteomics, Journal Year: 2024, Volume and Issue: 21(1)

Published: Nov. 1, 2024

COVID19 is a pandemic that has affected millions around the world since March 2020. While many patients recovered completely with mild illness, succumbed to various organ morbidities. This heterogeneity in clinical presentation of infection posed challenge clinicians world. It therefore crucial identify specific organ-related morbidity for effective treatment and better patient outcomes. We have carried out serum-based proteomic experiments protein biomarkers can flag dysfunctions patients.

Language: Английский

---

Clinical severity classes in COVID-19 pneumonia have distinct immunological profiles, facilitating risk stratification by machine learning

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 5, 2023

Objective Clinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during pandemic situation. However, risk stratification based serum biomarker bioprofiling could be implemented by larger, nonspecialist workforce. Method Measures of Complement Activation and inflammation patientS with CoronAvirus DisEase (CASCADE) patients ( n = 72), (clinicaltrials.gov: NCT04453527), classified as mild, moderate, or severe (by support needed to maintain SpO 2 > 93%), healthy controls (HC, 20), were bioprofiled using 76 immunological biomarkers compared ANOVA. Spearman correlation analysis pairs was visualised via heatmaps. Linear Discriminant Analysis (LDA) models generated identify likely deteriorate. An X-Gradient-boost (XGB) model trained CASCADE data retrospectively employed classify COROnavirus Nomacopan Emergency Treatment for covid 19 infected early signs respiratory distress (CORONET) 7) treated nomacopan. Results The LDA distinctly discriminated between deteriorators, nondeteriorators, HC, IL-27, IP-10, MDC, ferritin, C5, sC5b-9 among the key predictor variables deterioration. C3a C5 elevated all severity classes vs. HC p < 0.05). “moderate” “severe” categories 0.001). Heatmap shows pairwise increase negatively correlated IL-27. XGB indicated sC5b-9, IL-8, MCP1, prothrombin F1 F2 discriminators nomacopan-treated (CORONET study). Conclusion Distinct fingerprints from exist within different COVID-19, harnessing them machine learning enabled development clinically useful prognostic tools. Complement-mediated lung injury plays role COVID-19 pneumonia, preliminary results hint at usefulness inhibitor recovery.

Language: Английский

---