The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System

Świerzko, Anna St.; Cedzyński, Maciej

doi:10.3389/fimmu.2020.585243

Cited by 25 publications

(21 citation statements)

References 125 publications

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“…To activate the lectin pathway plasma-circulating lectins (collectins like mannan-binding lectin and ficolins) recognize carbohydrate patterns on the surface of microorganisms, called pathogen-associated molecular patterns (PAMPs). By binding dimers of mannan-binding lectin-associated serine protease 2 (MASP-2) these pattern-recognition molecules (PRM) form a complex which leads to the cleavage of C4 and C2 ( 17 , 18 ). In contrast, the alternative pathway is constantly active at a low level and is initiated by spontaneous hydrolysis of C3.…”

Section: Introductionmentioning

confidence: 99%

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19

et al. 2022

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Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.

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Section: Introductionmentioning

confidence: 99%

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19

et al. 2022

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“…Studies to date have used antibodies purified from patient samples, or cloned monoclonal antibodies, to detect phagocytosis, revealing a narrow pattern of antibody dependent phagocytosis without recognition of significant contribution of plasma proteins such as activated complement products that are recognised to be critical in phagocytic responses against other respiratory pathogens [11,17,18]. By contrast, in this study, native patient plasma was used revealing that the early phagocytic response in SARS-CoV-2 infection is primarily driven by heat labile components in the plasma, along with a contribution from Fc-receptor dependent antibody functions.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, little is known about the phagocytic responses during acute disease, and the long-term retention of these functions and the associated predictive factors in convalescent patients beyond five months are unknown [16]. Importantly, studies to date used purified patient antibodies or cloned monoclonal antibodies to detect phagocytosis and so disregarded potentially significant contribution of plasma proteins such as activated complements that are relevant in phagocytic responses against respiratory pathogens [11,17,18].…”

Section: Introductionmentioning

confidence: 99%

Longitudinal characterisation of phagocytic and neutralisation functions of anti-Spike antibodies in plasma of patients after SARS-CoV-2 infection

Adhikari

Abayasingam

Rodrigo

et al. 2021

Preprint

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Phagocytic responses by effector cells to antibody or complement-opsonised viruses have been recognized to play a key role in anti-viral immunity. These include antibody dependent cellular phagocytosis mediated via Fc-receptors, phagocytosis mediated by classically activated complement-fixing IgM or IgG1 antibodies and antibody independent phagocytosis mediated via direct opsonisation of viruses by complement products activated via the mannose-binding lectin pathway. Limited data suggest these phagocytic responses by effector cells may contribute to the immunological and inflammatory responses in SARS-CoV-2 infection, however, their development and clinical significance remain to be fully elucidated. In this cohort of 62 patients, acutely ill individuals were shown to mount phagocytic responses to autologous plasma-opsonised SARS-CoV-2 Spike protein-coated microbeads as early as 10 days post symptom onset. Heat inactivation of the plasma prior to use as an opsonin caused 77-95% abrogation of the phagocytic response, and pre-blocking of Fc-receptors on the effector cells showed only 18-60% inhibition. These results suggest that SARS-CoV-2 can provoke early phagocytosis, which is primarily driven by heat labile components, likely activated complements, with variable contribution from anti-Spike antibodies. During convalescence, phagocytic responses correlated significantly with anti-Spike IgG titers. Older patients and patients with severe disease had significantly higher phagocytosis and neutralisation functions when compared to younger patients or patients with asymptomatic, mild, or moderate disease. A longitudinal study of a subset of these patients over 12 months showed preservation of phagocytic and neutralisation functions in all patients, despite a drop in the endpoint antibody titers by more than 90%. Interestingly, surface plasmon resonance showed a significant increase in the affinity of the anti-Spike antibodies over time correlating with the maintenance of both the phagocytic and neutralisation functions suggesting that improvement in the antibody quality over the 12 months contributed to the retention of effector functions.

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“… 1 Single nucleotide polymorphism (SNP) position according to the database NCBI dbSNP HGVS (Human Genome Variation Society) names NM_000242.2:c entry; 2 SNP position used in the literature, e.g., Garred et al [ 8 ] or Świerzko and Cedzyński [ 18 ]; 3 Letter Y in the primer sequence indicates a site containing a degenerate base (cytosine or thymine). Single-base extension (SBE).…”

Section: Figurementioning

confidence: 99%

A SNaPshot Assay for Determination of the Mannose-Binding Lectin Gene Variants and an Algorithm for Calculation of Haplogenotype Combinations

Mrázková

Sistek²,

Lochman

et al. 2021

Diagnostics

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Mannose-binding lectin (MBL) deficiency caused by the variability in the MBL2 gene is responsible for the susceptibility to and severity of various infectious and autoimmune diseases. A combination of six single nucleotide polymorphisms (SNPs) has a major impact on MBL levels in circulation. The aim of this study is to design and validate a sensitive and economical method for determining MBL2 haplogenotypes. The SNaPshot assay is designed and optimized to genotype six SNPs (rs1800451, rs1800450, rs5030737, rs7095891, rs7096206, rs11003125) and is validated by comparing results with Sanger sequencing. Additionally, an algorithm for online calculation of haplogenotype combinations from the determined genotypes is developed. Three hundred and twenty-eight DNA samples from healthy individuals from the Czech population are genotyped. Minor allele frequencies (MAFs) in the Czech population are in accordance with those present in the European population. The SNaPshot assay for MBL2 genotyping is a high-throughput, cost-effective technique that can be used in further genetic-association studies or in clinical practice. Moreover, a freely available online application for the calculation of haplogenotypes from SNPs is developed within the scope of this project.

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The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System

Cited by 25 publications

References 125 publications

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19

Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19

Longitudinal characterisation of phagocytic and neutralisation functions of anti-Spike antibodies in plasma of patients after SARS-CoV-2 infection

A SNaPshot Assay for Determination of the Mannose-Binding Lectin Gene Variants and an Algorithm for Calculation of Haplogenotype Combinations

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