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

2020 ◽  
Vol 120 (12) ◽  
pp. 1720-1724 ◽  
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.

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

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
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.

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

mBio ◽  
2011 ◽  
Vol 2 (6) ◽  
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.

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

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

scholarly journals Mannose Binding Lectin Gene Deficiency Increases Susceptibility to Traumatic Brain Injury in Mice

2008 ◽  
Vol 28 (5) ◽  
pp. 1030-1039 ◽  
Author(s):  
Phoebe H Yager ◽  
Zerong You ◽  
Tao Qin ◽  
Hyung-Hwan Kim ◽  
Kazue Takahashi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Complement Activation ◽  
Ischemia Reperfusion ◽  
Mannose Binding Lectin ◽  
Motor Dysfunction ◽  
Cell Degeneration ◽  
Increased Risk ◽  
Mannose Binding ◽  
Binding Lectin

Mannose binding lectin (MBL) initiates complement activation and exacerbates tissue damage after systemic ischemia/reperfusion. We tested the hypothesis that MBL activates complement and worsens outcome using two levels of controlled cortical impact (CCI) in mice. After moderate CCI (0.6 mm depth), MBL immunostaining was detected on injured endothelial cells of wild-type (WT) mice and C3d was detected in MBL KO (deficient in MBL A/C) and WT mice, suggesting that MBL is dispensable for terminal complement activation after CCI. Brain neutrophils, edema, blood-brain barrier permeability, gross histopathology, and motor dysfunction were similar in injured MBL KO and WT mice. In mice subjected to mild CCI (0.2 mm), MBL KO mice had almost two-fold increased acute CA3 cell degeneration at 6 h ( P<0.01 versus WT). Naive MBL KO mice had decreased brain volume but performed similar to WT mice in two distinct Morris water maze (MWM) paradigms. However, injured MBL KO mice had impaired performance in cued platform trials (P<0.05 versus WT), suggesting a transient nonspatial learning deficit in injured MBL KO mice. The data suggest that MBL deficiency increases susceptibility to CCI through C3-independent mechanisms and that MBL-deficient patients may be at increased risk of poor outcome after traumatic brain injury.

Mannose-binding lectin genetics: from A to Z

2008 ◽  
Vol 36 (6) ◽  
pp. 1461-1466 ◽  
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.

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

2016 ◽  
Vol 21 (7) ◽  
pp. 749-757 ◽  
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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