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1.
Front Immunol ; 13: 835156, 2022.
Article in English | MEDLINE | ID: covidwho-1902991

ABSTRACT

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.


Subject(s)
COVID-19/immunology , Complement Pathway, Alternative/immunology , Lectins/immunology , Aged , Aged, 80 and over , Autopsy , COVID-19/pathology , COVID-19/virology , Complement System Proteins/immunology , Female , Humans , Kidney/immunology , Kidney/pathology , Kidney/virology , Lung/immunology , Lung/pathology , Lung/virology , Male , Middle Aged , Neutrophils/immunology , Peroxidase/immunology , SARS-CoV-2/immunology
2.
Genet Med ; 24(8): 1653-1663, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1819495

ABSTRACT

PURPOSE: Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. METHODS: Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. RESULTS: We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. CONCLUSION: This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.


Subject(s)
COVID-19 , Aged , COVID-19/genetics , Collectins/genetics , Collectins/metabolism , Germ Cells , Humans , Lectins/genetics , SARS-CoV-2 , Whole Exome Sequencing
3.
Front Immunol ; 12: 742446, 2021.
Article in English | MEDLINE | ID: covidwho-1441112

ABSTRACT

Background: The 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. Methods: We 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. Results: Four 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. Conclusion: These 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.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Complement Pathway, Mannose-Binding Lectin , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Complement System Proteins/immunology , Female , Humans , Male , Middle Aged , Retrospective Studies
5.
Front Immunol ; 12: 714511, 2021.
Article in English | MEDLINE | ID: covidwho-1320579

ABSTRACT

Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.


Subject(s)
COVID-19/blood , Complement Activation/immunology , Complement System Proteins/metabolism , Lectins/blood , Renal Insufficiency, Chronic/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/complications , COVID-19/pathology , COVID-19/physiopathology , Cohort Studies , Complement System Proteins/immunology , Female , Humans , Male , Middle Aged , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/virology , Severity of Illness Index
6.
J Clin Med ; 10(10)2021 May 19.
Article in English | MEDLINE | ID: covidwho-1234756

ABSTRACT

Severe coronavirus disease 2019 causes multi-organ dysfunction with significant morbidity and mortality. Mounting evidence implicates maladaptive over-activation of innate immune pathways such as the complement cascade as well as endothelial dysfunction as significant contributors to disease progression. We review the complement pathways, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on these pathways, and promising therapeutic targets in clinical trials.

7.
Front Immunol ; 11: 594849, 2020.
Article in English | MEDLINE | ID: covidwho-1083385

ABSTRACT

Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.


Subject(s)
Acute Kidney Injury/immunology , Acute Kidney Injury/virology , COVID-19/complications , COVID-19/immunology , Complement Activation/physiology , Adult , Aged , Female , Humans , Male , Middle Aged , SARS-CoV-2
8.
Clin Immunol ; 219: 108555, 2020 10.
Article in English | MEDLINE | ID: covidwho-696063

ABSTRACT

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Subject(s)
Acute Kidney Injury/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/pathogenicity , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Pneumonia, Viral/immunology , Severe Acute Respiratory Syndrome/immunology , Acute Kidney Injury/complications , Acute Kidney Injury/drug therapy , Acute Kidney Injury/virology , Adult , Betacoronavirus/immunology , Biomarkers/metabolism , COVID-19 , Complement Activation/drug effects , Complement C4b/antagonists & inhibitors , Complement C5/antagonists & inhibitors , Complement Membrane Attack Complex/antagonists & inhibitors , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Immunity, Humoral/drug effects , Male , Mannose-Binding Protein-Associated Serine Proteases/genetics , Mannose-Binding Protein-Associated Serine Proteases/immunology , Middle Aged , Neutrophils/immunology , Neutrophils/pathology , Pandemics , Peptide Fragments/antagonists & inhibitors , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/virology
9.
Immunobiology ; 225(6): 152001, 2020 11.
Article in English | MEDLINE | ID: covidwho-696536

ABSTRACT

In COVID-19, acute respiratory distress syndrome (ARDS) and thrombotic events are frequent, life-threatening complications. Autopsies commonly show arterial thrombosis and severe endothelial damage. Endothelial damage, which can play an early and central pathogenic role in ARDS and thrombosis, activates the lectin pathway of complement. Mannan-binding lectin-associated serine protease-2 (MASP-2), the lectin pathway's effector enzyme, binds the nucleocapsid protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), resulting in complement activation and lung injury. Narsoplimab, a fully human immunoglobulin gamma 4 (IgG4) monoclonal antibody against MASP-2, inhibits lectin pathway activation and has anticoagulant effects. In this study, the first time a lectin-pathway inhibitor was used to treat COVID-19, six COVID-19 patients with ARDS requiring continuous positive airway pressure (CPAP) or intubation received narsoplimab under compassionate use. At baseline and during treatment, circulating endothelial cell (CEC) counts and serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed. Narsoplimab treatment was associated with rapid and sustained reduction of CEC and concurrent reduction of serum IL-6, IL-8, CRP and LDH. Narsoplimab was well tolerated; no adverse drug reactions were reported. Two control groups were used for retrospective comparison, both showing significantly higher mortality than the narsoplimab-treated group. All narsoplimab-treated patients recovered and survived. Narsoplimab may be an effective treatment for COVID-19 by reducing COVID-19-related endothelial cell damage and the resultant inflammation and thrombotic risk.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/immunology , Complement Pathway, Mannose-Binding Lectin/drug effects , Endothelium, Vascular/drug effects , SARS-CoV-2/immunology , Thrombotic Microangiopathies/drug therapy , Antibodies, Monoclonal/immunology , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/complications , COVID-19/virology , Complement Pathway, Mannose-Binding Lectin/immunology , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Female , Humans , Immunoglobulin G/immunology , Immunoglobulin G/therapeutic use , Inflammation/complications , Inflammation/immunology , Inflammation/prevention & control , Interleukin-6/blood , Interleukin-6/immunology , Male , Mannose-Binding Protein-Associated Serine Proteases/antagonists & inhibitors , Mannose-Binding Protein-Associated Serine Proteases/immunology , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Retrospective Studies , SARS-CoV-2/physiology , Thrombotic Microangiopathies/complications , Thrombotic Microangiopathies/immunology
10.
EMBO Mol Med ; 12(8): e12642, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-607958

ABSTRACT

A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.


Subject(s)
Betacoronavirus , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Adult , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/physiology , COVID-19 , Child , Complement C3b/antagonists & inhibitors , Complement C3b/physiology , Complement Inactivating Agents/pharmacology , Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Glycosylation , Humans , Immunity, Innate , Ligands , Mice , Models, Animal , Models, Molecular , Pattern Recognition, Automated , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Protein Conformation , Protein Processing, Post-Translational , Receptors, Virus/metabolism , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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