Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality

BackgroundThe SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes.MethodsWe conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality.ResultsFour clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group.ConclusionThese findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.

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Components of the Lectin Pathway of Complement in Haematologic Malignancies

Cancers ◽

10.3390/cancers12071792 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1792

Author(s):

Maciej Cedzyński ◽

Anna S. Świerzko

Keyword(s):

Serine Proteases ◽

Proteolytic Enzymes ◽

Alternative Pathway ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Classical Pathway ◽

Mannose Binding ◽

Molecular Patterns ◽

Binding Lectin ◽

Haematologic Malignancies

The complement system is activated cascadically via three distinct major routes: classical pathway (CP), alternative pathway (AP) or lectin pathway (LP). The unique factors associated with the latter are collectins (mannose-binding lectin, collectin-10, collectin-11), ficolins (ficolin-1, ficolin-2, ficolin-3) and proteins of the mannose-binding lectin-associated serine protease (MASP) family (MASP-1, MASP-2, MASP-3, MAp19, MAp44). Collectins and ficolins are both pattern-recognising molecules (PRM), reactive against pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP). The MASP family proteins were first discovered as complexes with mannose-binding lectin (MBL) and therefore named MBL-associated serine proteases, but later, they were found to interact with ficolins, and later still, collectin-10 and collectin-11. As well as proteolytic enzymes (MASP-1, MASP-2, MASP-3), the group includes non-enzymatic factors (MAp19, MAp44). In this review, the association-specific factors of the lectin pathway with haematologic malignancies and related infections are discussed.

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Mannose-binding lectin genetics: from A to Z

Biochemical Society Transactions ◽

10.1042/bst0361461 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1461-1466 ◽

Cited By ~ 75

Author(s):

Peter Garred

Keyword(s):

Epidemiological Studies ◽

Mannose Binding Lectin ◽

Host Cells ◽

Lectin Pathway ◽

Mannose Binding ◽

The Stability ◽

Genetically Determined ◽

Micro Organisms ◽

Binding Lectin

MBL (mannose-binding lectin) is primarily a liver-derived collagen-like serum protein. It binds sugar structures on micro-organisms and on dying host cells and is one of the four known mediators that initiate activation of the complement system via the lectin pathway. Common variant alleles situated both in promoter and structural regions of the human MBL gene (MBL2) influence the stability and the serum concentration of the protein. Epidemiological studies have suggested that genetically determined variations in MBL serum concentrations influence the susceptibility to and the course of different types of infectious, autoimmune, neoplastic, metabolic and cardiovascular diseases, but this is still a subject under discussion. The fact that these genetic variations are very frequent, indicates a dual role of MBL. This overview summarizes the current molecular understanding of human MBL2 genetics.

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A New Surface Plasmon Resonance Assay for In Vitro Screening of Mannose-Binding Lectin Inhibitors

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057116637563 ◽

2016 ◽

Vol 21 (7) ◽

pp. 749-757 ◽

Cited By ~ 4

Author(s):

Matteo Stravalaci ◽

Daiana De Blasio ◽

Franca Orsini ◽

Carlo Perego ◽

Alessandro Palmioli ◽

...

Keyword(s):

Surface Plasmon Resonance ◽

Surface Plasmon ◽

Plasmon Resonance ◽

Ischemia Reperfusion ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

In Vitro Screening ◽

Mannose Binding ◽

Binding Lectin

Mannose-binding lectin (MBL) is a circulating protein that acts as a soluble pattern recognition molecule of the innate immunity. It binds to carbohydrate patterns on the surface of pathogens or of altered self-cells, with activation of the lectin pathway of the complement system. Recent evidence indicates that MBL contributes to the pathophysiology of ischemia-reperfusion injury and other conditions. Thus, MBL inhibitors offer promising therapeutic strategies, since they prevent the interaction of MBL with its target sugar arrays. We developed and characterized a novel assay based on surface plasmon resonance for in vitro screening of these compounds, which may be useful before the more expensive and time-consuming in vivo studies. The assay measures the inhibitor’s ability to interfere with the binding of murine MBL-A or MBL-C, or of human recombinant MBL, to mannose residues immobilized on the sensor chip surface. We have applied the assay to measure the IC50 of synthetic glycodendrimers, two of them with neuroprotective properties in animal models of MBL-mediated injuries.

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L-Ficolin/Mannose-Binding Lectin-Associated Serine Protease Complexes Bind to Group B Streptococci Primarily through N-Acetylneuraminic Acid of Capsular Polysaccharide and Activate the Complement Pathway

Infection and Immunity ◽

10.1128/iai.00837-07 ◽

2007 ◽

Vol 76 (1) ◽

pp. 179-188 ◽

Cited By ~ 34

Author(s):

Youko Aoyagi ◽

Elisabeth E. Adderson ◽

Craig E. Rubens ◽

John F. Bohnsack ◽

Jin G. Min ◽

...

Keyword(s):

Serine Protease ◽

Specific Antibody ◽

Capsular Polysaccharide ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Group B Streptococci ◽

Acetylneuraminic Acid ◽

Mannose Binding ◽

Group B ◽

Binding Lectin

ABSTRACT Group B streptococci (GBS) are the most common cause of neonatal sepsis and meningitis. Most infants who are colonized with GBS at birth do not develop invasive disease, although many of these uninfected infants lack protective levels of capsular polysaccharide (CPS)-specific antibody. The lectin pathway of complement is a potential mechanism for initiating opsonization of GBS with CPS-specific antibody-deficient serum. In this study, we determined whether mannose-binding lectin (MBL)/MBL-associated serine protease (MASP) complexes and L-ficolin/MASP complexes bind to different strains of GBS to activate the lectin pathway, and we identified the molecules recognized by lectins on the GBS surface. We found that MBL did not bind to any GBS examined, whereas L-ficolin bound to GBS cells of many serotypes. L-ficolin binding to GBS cells correlated with the CPS content in serotypes Ib, III (restriction digestion pattern types III-2 and III-3), and V but not with the group B-specific polysaccharide (GBPS) content or with the lipoteichoic acid (LTA) content. L-ficolin bound to purified CPS and GBPS in a concentration-dependent manner but not to purified LTA. All strains to which L-ficolin/MASP complexes bound consumed C4. When N-acetylneuraminic acid (NeuNAc) was selectively removed from GBS cells by treatment with neuraminidase, the reduction in L-ficolin binding was correlated with the amount of NeuNAc removed. Additionally, L-ficolin was able to bind to wild-type strains but was able to bind only weakly to unencapsulated mutants and a mutant strain in which the CPS lacks NeuNAc. We concluded that L-ficolin/MASP complexes bind to GBS primarily through an interaction with NeuNAc of CPS.

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Mannose-Binding Lectin Pathway

Encyclopedia of Immunotoxicology ◽

10.1007/978-3-642-54596-2_200951 ◽

2015 ◽

pp. 580-580

Keyword(s):

Mannose Binding Lectin ◽

Lectin Pathway ◽

Mannose Binding ◽

Binding Lectin

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Mannose-Binding Lectin is Associated with Thrombosis and Coagulopathy in Critically Ill COVID-19 Patients

Thrombosis and Haemostasis ◽

10.1055/s-0040-1715835 ◽

2020 ◽

Vol 120 (12) ◽

pp. 1720-1724 ◽

Cited By ~ 1

Author(s):

Michael Hultström ◽

Robert Frithiof ◽

Oskar Eriksson ◽

Barbro Persson ◽

Miklos Lipcsey ◽

...

Keyword(s):

Critically Ill ◽

Complement Activation ◽

Tertiary Hospital ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Strongly Correlated ◽

Increased Risk ◽

Mannose Binding ◽

Patients At Risk ◽

Binding Lectin

AbstractThe ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society. COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis. The mechanism behind COVID-19-associated coagulopathy remains unclear. Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation. Here we describe data from a cohort of critically ill COVID-19 patients (n = 65) treated at a tertiary hospital center intensive care unit (ICU). A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE. MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction. In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients. Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19. Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events.

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Impact of Mannose-Binding Lectin Deficiency on Radiocontrast-Induced Renal Dysfunction

BioMed Research International ◽

10.1155/2013/962695 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Michael Osthoff ◽

Marten Trendelenburg

Keyword(s):

Endothelial Dysfunction ◽

Renal Dysfunction ◽

Serine Proteases ◽

Vascular Endothelial Cells ◽

Ischemia Reperfusion ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Increased Risk ◽

Mannose Binding ◽

Binding Lectin

Contrast-induced nephropathy (CIN) is the third leading cause of acute renal failure in hospitalized patients. Endothelial dysfunction, renal medullary ischemia, and tubular toxicity are regarded as the most important factors in the pathogenesis of CIN. Mannose-binding lectin (MBL), a pattern recognition protein of the lectin pathway of complement, has been found to aggravate and mediate tissue damage during experimental renal ischemia/reperfusion (I/R) injury which was alleviated by inhibition with C1 inhibitor, a potent MBL, and lectin pathway inhibitor. In this paper, we highlight the potential role of MBL in the pathogenesis of human CIN. In experimental I/R models, MBL was previously found to induce tubular cell death independent of the complement system. In addition, after binding to vascular endothelial cells, MBL and its associated serine proteases were able to trigger a proinflammatory reaction and contribute to endothelial dysfunction. In humans, urinary MBL was increased after administration of contrast media and in individuals with CIN. Moreover, individuals with normal/high MBL levels were at increased risk to develop radiocontrast-induced renal dysfunction. Hence, MBL and the lectin pathway seem to be a promising target given that a licensed, powerful, human recombinant inhibitor exits to be added to the scarce armamentarium currently available for prophylaxis of CIN.

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A Novel and Pivotal Role of the Mannose-Binding Lectin (MBL) Pathway of Complement Cascade (ComC) Activation in Triggering Mobilization of Hematopoietic Stem/Progenitor Cells (HSPCs)

Blood ◽

10.1182/blood.v126.23.4301.4301 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4301-4301 ◽

Cited By ~ 1

Author(s):

Mateusz Adamiak ◽

Ahmed Abdel-Latif ◽

Janina Ratajczak ◽

Mariusz Z Ratajczak

Keyword(s):

Pattern Recognition ◽

Mannose Binding Lectin ◽

Pivotal Role ◽

Classical Pathway ◽

Complement Cascade ◽

Alternative Pathways ◽

Mannose Binding ◽

Binding Lectin ◽

Mbl Deficiency

Abstract Background . The complement cascade (ComC) is part of the innate immunity system, which is not adaptable and does not change over the course of an individual's lifetime; however, it can be recruited and brought into action by the adaptive immune system. The ComC has several pleiotropic effects, and, as we have previously demonstrated, it is required for mobilization of HSPCs during infection or tissue/organ injuries and responding to pharmacological mobilizing agents (Blood 2004, 103, 2071-2078). The ComC is activated by three pathways: the classical, alternative, and mannose-binding lectin (MBL) pathways. While a requirement for ComC activation and, in particular, the pivotal role of the distal part of complement activation and generation of C5 cleavage fragments was previously demonstrated by us (Leukemia 2009, 23, 2052-2062), mice with mutations to components of the classical and alternative pathways in which the distal pathway of C5 activation remained intact did not show impairment of HSPC mobilization (Leukemia 2010, 24, 1667-1675). However, no studies so far have been performed to address the role of the MBL pathway of ComC activation in triggering the mobilization of HSPCs. The MBL pathway is homologous to the classical pathway, but contains opsonin, MBL, and ficolins instead of C1q. MBL functions by pattern recognition, as opsonin binds to mannose residues on the surface of pathogens and certain cells, and activates the MBL-associated serine proteases, MASP-1, and MASP-2, which can then split C4 (into C4a and C4b) and C2 (into C2a and C2b) to form the classical C3-convertase, as in the classical pathway. Interestingly, it is known that ~10% of the population has defective activation of the MBL pathway. Hypothesis. We hypothesized for first time that the MBL ComC-activation pathway is involved in triggering ComC-mediated mobilization of HSPCs and that MBL deficiency results in poor mobilization. Materials and Methods . In our experiments, 2-month-old, MBL-deficient mice (MBL-/-) and normal wild type (WT) littermates were mobilized for 6 days with G-CSF or AMD3100. Following mobilization, we measured in peripheral blood (PB) i) the total number of white blood cells (WBC), ii) the number of circulating clonogenic colony-forming unit granulocyte/macrophage (CFU-GM) progenitors, and iii) the number of Sca-1+ c-kit+ lineage- (SKL) cells. In parallel, we evaluated activation of the MBL pathway in WT animals after administration of G-CSF and AMD3100. Results . We found that pattern recognition by the MBL ComC activation pathway is involved in pharmacological G-CSF- and AMD3100-induced mobilization of HSPCs, and activation of the MBL pathway was confirmed by ELISA in WT animals. As predicted, MBL KO mice were found to be poor mobilizers. Conclusions . We identified a previously unrecognized role of the MBL pathway in triggering ComC activation in the process of HSPC mobilization. This finding explains the pivotal role of the MBL pathway in triggering activation of the proximal part of the ComC and explains why, even with a deficiency in activation of classical and alternative pathway components, mobilization of HSPCs proceeds normally as long as the MBL pathway is intact. On the other hand, if the MBL pathway of the ComC is defective, neither classical nor alternative pathways can trigger optimal mobilization of HSPCs. Taking into consideration that ~10% of normal people are poor activators of the MBL pathway, we are currently investigating whether MBL deficiency correlates with poor mobilization in these patients. Disclosures No relevant conflicts of interest to declare.

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