Interactions between mannose-binding lectin and MASPs during complement activation by the lectin pathway

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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Complement-Mediated Neutralization of Dengue Virus Requires Mannose-Binding Lectin

mBio ◽

10.1128/mbio.00276-11 ◽

2011 ◽

Vol 2 (6) ◽

Cited By ~ 45

Author(s):

Panisadee Avirutnan ◽

Richard E. Hauhart ◽

Mary A. Marovich ◽

Peter Garred ◽

John P. Atkinson ◽

...

Keyword(s):

Dengue Virus ◽

Human Serum ◽

Complement Activation ◽

Insect Cell ◽

Denv Infection ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Denv Serotypes ◽

Mannose Binding ◽

Binding Lectin

ABSTRACTMannose-binding lectin (MBL) is a key soluble pathogen recognition protein of the innate immune system that binds specific mannose-containing glycans on the surfaces of microbial agents and initiates complement activation via the lectin pathway. Prior studies showed that MBL-dependent activation of the complement cascade neutralized insect cell-derived West Nile virus (WNV) in cell culture and restricted pathogenesis in mice. Here, we investigated the antiviral activity of MBL in infection by dengue virus (DENV), a related flavivirus. Using a panel of naïve sera from mouse strains deficient in different complement components, we showed that inhibition of infection by insect cell- and mammalian cell-derived DENV was primarily dependent on the lectin pathway. Human MBL also bound to DENV and neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Experiments with human serum from naïve individuals with inherent variation in the levels of MBL in blood showed a direct correlation between the concentration of MBL and neutralization of DENV; samples with high levels of MBL in blood neutralized DENV more efficiently than those with lower levels. Our studies suggest that allelic variation of MBL in humans may impact complement-dependent control of DENV pathogenesis.IMPORTANCEDengue virus (DENV) is a mosquito-transmitted virus that causes a spectrum of clinical disease in humans ranging from subclinical infection to dengue hemorrhagic fever and dengue shock syndrome. Four serotypes of DENV exist, and severe illness is usually associated with secondary infection by a different serotype. Here, we show that mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Moreover, we observed a direct correlation with the concentration of MBL in human serum and neutralization of DENV infection. Our studies suggest that common genetic polymorphisms that result in disparate levels and function of MBL in humans may impact DENV infection, pathogenesis, and disease severity.

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The mannose binding lectin pathway and early complement activation in (murine) abortion

Journal of Reproductive Immunology ◽

10.1016/j.jri.2010.08.037 ◽

2010 ◽

Vol 86 (2) ◽

pp. 98-99

Author(s):

Marie Petitbarat ◽

Sylvie Dubanchet ◽

Roberta Bulla ◽

Olivier Sandra ◽

Nathalie Lédée ◽

...

Keyword(s):

Complement Activation ◽

Mannose Binding Lectin ◽

Lectin Pathway ◽

Mannose Binding ◽

Binding Lectin

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The Mannose-Binding Lectin-Pathway Is Involved in Complement Activation in the Course of Renal Ischemia-Reperfusion Injury

American Journal Of Pathology ◽

10.1016/s0002-9440(10)63424-4 ◽

2004 ◽

Vol 165 (5) ◽

pp. 1677-1688 ◽

Cited By ~ 146

Author(s):

Bart de Vries ◽

Sarah J. Walter ◽

Carine J. Peutz-Kootstra ◽

Tim G.A.M. Wolfs ◽

L.W. Ernest van Heurn ◽

...

Keyword(s):

Reperfusion Injury ◽

Complement Activation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mannose Binding Lectin ◽

Renal Ischemia ◽

Lectin Pathway ◽

Renal Ischemia Reperfusion Injury ◽

Mannose Binding ◽

Binding Lectin

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Faculty Opinions recommendation of Mannose binding lectin plays a crucial role in innate immunity against yeast by enhanced complement activation and enhanced uptake of polymorphonuclear cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1138065.595179 ◽

2008 ◽

Author(s):

Steven Witkin

Keyword(s):

Innate Immunity ◽

Complement Activation ◽

Crucial Role ◽

Mannose Binding Lectin ◽

Polymorphonuclear Cells ◽

Mannose Binding ◽

Binding Lectin

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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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