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1.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1715404

ABSTRACT

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.


Subject(s)
Apolipoproteins/metabolism , Caspases/metabolism , Complement System Proteins/metabolism , Cytokines/metabolism , alpha 1-Antitrypsin/metabolism , Binding Sites/genetics , COVID-19/metabolism , COVID-19/virology , Glycosylation , Humans , Mutation , Protein Binding , Protein Domains , SARS-CoV-2/physiology , alpha 1-Antitrypsin/chemistry , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin Deficiency/metabolism
2.
Commun Biol ; 5(1): 152, 2022 02 22.
Article in English | MEDLINE | ID: covidwho-1701655

ABSTRACT

The complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g., COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may be alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH, including SCR 13. In summary, the fusion protein MFHR13 comprises SCRs FHR11-2:FH1-4:FH13:FH19-20. It protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as therapeutic for complement-associated diseases.


Subject(s)
Blood Proteins/metabolism , Complement Activation , Complement Factor H/metabolism , Complement System Proteins/metabolism , Erythrocytes/metabolism , Recombinant Fusion Proteins/metabolism , Amino Acid Sequence , Animals , Bryopsida/genetics , Bryopsida/metabolism , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Complement Membrane Attack Complex/metabolism , Humans , Models, Molecular , Pandemics/prevention & control , Protein Binding , Protein Conformation , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , SARS-CoV-2/physiology , Sheep
3.
Viruses ; 14(1)2021 12 24.
Article in English | MEDLINE | ID: covidwho-1576961

ABSTRACT

Little is known about the role of complement (C') in infections with highly prevalent circulating human coronaviruses such as OC43, a group of viruses of major public health concern. Treatment of OC43-infected human lung cells with human serum resulted in C3 deposition on their surfaces and generation of C5a, indicating robust C' activation. Real-time cell viability assays showed that in vitro C'-mediated lysis of OC43 infected cells requires C3, C5 and C6 but not C7, and was substantially delayed as compared to rapid C'-mediated killing of parainfluenza virus type 5 (PIV5)-infected cells. In cells co-infected with OC43 and PIV5, C'-mediated lysis was delayed, similar to OC43 infected cells alone, suggesting that OC43 infection induced dominant inhibitory signals. When OC43-infected cells were treated with human serum, their cell surfaces contained both Vitronectin (VN) and Clusterin (CLU), two host cell C' inhibitors that can alter membrane attack complex (MAC) formation and C'-mediated killing. VN and CLU were not bound to OC43-infected cells after treatment with antibody-depleted serum. Reconstitution experiments with purified IgG and VN showed that human antibodies are both necessary and sufficient for VN recruitment to OC43-infected lung cells-novel findings with implications for CoV pathogenesis.


Subject(s)
Antibodies/metabolism , Clusterin/metabolism , Complement Inactivator Proteins/metabolism , Coronavirus OC43, Human/immunology , Lung/virology , Vitronectin/metabolism , Cell Line , Cell Membrane/metabolism , Cell Survival/immunology , Complement Activation , Complement Membrane Attack Complex/metabolism , Complement System Proteins/metabolism , Coronavirus OC43, Human/pathogenicity , Humans , Lung/metabolism , Parainfluenza Virus 5/immunology
4.
Int J Immunopathol Pharmacol ; 35: 20587384211048026, 2021.
Article in English | MEDLINE | ID: covidwho-1440891

ABSTRACT

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/immunology , COVID-19/physiopathology , Complement Activation , Complement System Proteins/metabolism , Cytokines/blood , Disease Progression , Host-Pathogen Interactions , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/physiopathology , Inflammation/virology , Inflammation Mediators/blood , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/immunology , Macrophage Activation Syndrome/physiopathology , Macrophage Activation Syndrome/virology , Platelet Activation , SARS-CoV-2/immunology , Serotonin/blood , Severity of Illness Index , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/physiopathology , Thrombotic Microangiopathies/virology
5.
Adv Biol Regul ; 81: 100822, 2021 08.
Article in English | MEDLINE | ID: covidwho-1364204

ABSTRACT

Severe COVID-19 is characterized by lung and multiorgan inflammation and coagulation in the presence of overactivation of the complement system. Complement is a double edged-sward in SARS-Cov-2 infection. On one hand, it can control the viral infection in milder cases, on the other hand in cases with severe and prolonged infection massive complement activation occurs, which can intensify lung and systemic inflammation and promote a procoagulant and prothrombotic state. Several uncontrolled studies and controlled clinical trials with different complement inhibitors have been performed and others are ongoing. Results are promising in some but negative in others. Further studies are required to elucidate the benefit to risk profile of complement inhibitors in COVID-19 patients at different stages of the disease and to clarify the best targets in the complement cascade.


Subject(s)
COVID-19/blood , COVID-19/drug therapy , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Complement System Proteins/metabolism , SARS-CoV-2/metabolism , Humans , Lung/metabolism , Lung/pathology , Severity of Illness Index
6.
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
7.
Clin Immunol ; 229: 108795, 2021 08.
Article in English | MEDLINE | ID: covidwho-1305213

ABSTRACT

Acute and chronic kidney failure is common in hospitalized patients with COVID-19, yet the mechanism of injury and predisposing factors remain poorly understood. We investigated the role of complement activation by determining the levels of deposited complement components (C1q, C3, FH, C5b-9) and immunoglobulin along with the expression levels of the injury-associated molecules spleen tyrosine kinase (Syk), mucin-1 (MUC1) and calcium/calmodulin-dependent protein kinase IV (CaMK4) in the kidney tissues of people who succumbed to COVID-19. We report increased deposition of C1q, C3, C5b-9, total immunoglobulin, and high expression levels of Syk, MUC1 and CaMK4 in the kidneys of COVID-19 patients. Our study provides strong rationale for the expansion of trials involving the use of inhibitors of these molecules, in particular C1q, C3, Syk, MUC1 and CaMK4 to treat patients with COVID-19.


Subject(s)
COVID-19/metabolism , Complement System Proteins/metabolism , Kidney/metabolism , Mucin-1/metabolism , SARS-CoV-2 , Syk Kinase/metabolism , Aged , Aged, 80 and over , COVID-19/pathology , Calcium-Calmodulin-Dependent Protein Kinase Type 4/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism , Complement System Proteins/genetics , Fatal Outcome , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Mucin-1/genetics , Syk Kinase/genetics
8.
Int J Mol Sci ; 22(11)2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1256567

ABSTRACT

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.


Subject(s)
COVID-19/pathology , Lipoproteins, HDL/metabolism , Sepsis/pathology , Acute Kidney Injury/etiology , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Cholesterol/metabolism , Complement System Proteins/metabolism , Humans , Lipid Metabolism , Lipoproteins, HDL/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Sepsis/complications , Sepsis/metabolism , Virus Internalization
9.
Front Immunol ; 12: 665300, 2021.
Article in English | MEDLINE | ID: covidwho-1226978

ABSTRACT

The irruption of SARS-CoV-2 during 2020 has been of pandemic proportions due to its rapid spread and virulence. COVID-19 patients experience respiratory, digestive and neurological symptoms. Distinctive symptom as anosmia, suggests a potential neurotropism of this virus. Amongst the several pathways of entry to the nervous system, we propose an alternative pathway from the infection of the gut, involving Toll-like receptor 4 (TLR4), zonulin, protease-activated receptor 2 (PAR2) and zonulin brain receptor. Possible use of zonulin antagonists could be investigated to attenuate neurological manifestations caused by SARS-CoV-19 infection.


Subject(s)
COVID-19/complications , Haptoglobins/metabolism , Nervous System Diseases/complications , Protein Precursors/metabolism , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/virology , Brain/metabolism , Brain/virology , COVID-19/metabolism , COVID-19/virology , Complement System Proteins/metabolism , Gastrointestinal Diseases/complications , Gastrointestinal Diseases/metabolism , Gastrointestinal Diseases/virology , Humans , Nervous System Diseases/metabolism , Nervous System Diseases/virology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Toll-Like Receptor 4/metabolism
10.
Front Immunol ; 11: 573583, 2020.
Article in English | MEDLINE | ID: covidwho-1226976

ABSTRACT

Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.


Subject(s)
Adaptive Immunity , Complement Activation , Complement System Proteins/immunology , Immunity, Innate , RNA Virus Infections/virology , RNA Viruses/pathogenicity , Animals , Complement System Proteins/genetics , Complement System Proteins/metabolism , Evolution, Molecular , Gene Expression Regulation, Viral , Host-Pathogen Interactions , Humans , RNA Virus Infections/genetics , RNA Virus Infections/immunology , RNA Virus Infections/mortality , RNA Viruses/genetics , RNA Viruses/immunology , Severity of Illness Index
11.
Biomolecules ; 11(5)2021 05 06.
Article in English | MEDLINE | ID: covidwho-1223942

ABSTRACT

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.


Subject(s)
COVID-19/pathology , Extracellular Traps/metabolism , Thrombosis/immunology , Thrombosis/pathology , Biomarkers/metabolism , COVID-19/immunology , COVID-19/virology , Complement System Proteins/metabolism , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/pathology , Humans , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , SARS-CoV-2/isolation & purification , Thrombosis/metabolism
13.
Cell Rep Med ; 2(5): 100275, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1193507

ABSTRACT

Many SARS-CoV-2-infected individuals remain asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mildly symptomatic, and 21 hospitalized patients with COVID-19. We measure anti-spike immunoglobulin G (IgG), IgA, and IgM levels with the S-Flow assay and map IgG-targeted epitopes with a Luminex assay. We also evaluate neutralization, complement deposition, and antibody-dependent cellular cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC, and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than they are in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.


Subject(s)
Antibodies, Viral/blood , COVID-19/pathology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Antibodies, Viral/immunology , Antibody-Dependent Cell Cytotoxicity , Antigen-Antibody Reactions , Asymptomatic Diseases , COVID-19/virology , Complement System Proteins/metabolism , Epitopes/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Killer Cells, Natural/immunology , Male , Middle Aged , Neutralization Tests , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Young Adult
14.
mBio ; 12(2)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1148106

ABSTRACT

Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases.IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.


Subject(s)
Bacterial Proteins/metabolism , Bordetella pertussis/pathogenicity , Complement C1 Inhibitor Protein/metabolism , Immune Evasion , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Binding Sites , Blood Coagulation , Bordetella pertussis/chemistry , Bordetella pertussis/metabolism , Complement C1 Inhibitor Protein/chemistry , Complement System Proteins/metabolism , Cryoelectron Microscopy , Fibrinolysis , Models, Molecular , Mutation , Protein Binding , Protein Domains , Type V Secretion Systems/genetics , Type V Secretion Systems/metabolism , Virulence , Virulence Factors, Bordetella
15.
Mol Cell Biochem ; 476(8): 2917-2942, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1141473

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a virus called "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)." In the majority of patients, infection with COVID-19 may be asymptomatic or may cause only mild symptoms. However, in some patients, there can also be immunological problems, such as macrophage activation syndrome (CSS) that results in cytokine storm syndrome (CSS) and acute respiratory distress syndrome (ARDS). Comprehension of host-microbe communications is the critical aspect in the advancement of new therapeutics against infectious illnesses. Endogenous animal lectins, a class of proteins, may perceive non-self glycans found on microorganisms. Serum mannose-binding lectin (sMBL), as a part of the innate immune framework, recognizes a wide range of microbial microorganisms and activates complement cascade via an antibody-independent pathway. Although the molecular basis for the intensity of SARS-CoV-2 infection is not generally understood, scientific literature indicates that COVID-19 is correlated with unregulated activation of the complement in terms of disease severity. Disseminated intravascular coagulation (DIC), inflammation, and immune paralysis contribute to unregulated complement activation. Pre-existing genetic defects in MBL and their association with complement play a major role in immune response dysregulation caused by SARS-CoV-2. In order to generate anti-complement-based therapies in Covid-19, an understanding of sMBL in immune response to SARS-CoV-2 and complement is therefore essential. This review highlights the role of endogenous sMBL and complement activation during SARS-CoV-2 infection and their therapeutic management by various agents, mainly plant lectins, since antiviral mannose-binding plant lectins (pMBLs) offer potential applications in the prevention and control of viral infections.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Complement System Proteins/metabolism , Mannose-Binding Lectin/metabolism , Antiviral Agents/pharmacology , COVID-19/blood , COVID-19/immunology , Host-Pathogen Interactions/drug effects , Humans , Mannose-Binding Lectin/blood , Mannose-Binding Lectin/chemistry , Mannose-Binding Lectin/deficiency , SARS-CoV-2/drug effects
16.
Scand J Immunol ; 93(6): e13024, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1091011

ABSTRACT

Early airway responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are of interest since they could decide whether coronavirus disease-19 (COVID-19) will proceed to life-threatening pulmonary disease stages. Here I discuss endothelial-epithelial co-operative in vivo responses producing first-line, humoral innate defence opportunities in human airways. The pseudostratified epithelium of human nasal and tracheobronchial airways are prime sites of exposure and infection by SARS-CoV-2. Just beneath the epithelium runs a profuse systemic microcirculation. Its post-capillary venules respond conspicuously to mucosal challenges with autacoids, allergens and microbes, and to mere loss of epithelium. By active venular endothelial gap formation, followed by transient yielding of epithelial junctions, non-sieved plasma macromolecules move from the microcirculation to the mucosal surface. Hence, plasma-derived protein cascade systems and antimicrobial peptides would have opportunity to operate jointly on an unperturbed mucosal lining. Similarly, a plasma-derived, dynamic gel protects sites of epithelial sloughing-regeneration. Precision for this indiscriminate humoral molecular response lies in restricted location and well-regulated duration of plasma exudation. Importantly, the endothelial responsiveness of the airway microcirculation differs distinctly from the relatively non-responsive, low-pressure pulmonary microcirculation that non-specifically, almost irreversibly, leaks plasma in life-threatening COVID-19. Observations in humans of infections with rhinovirus, coronavirus 229E, and influenza A and B support a general but individually variable early occurrence of plasma exudation in human infected nasal and tracheobronchial airways. Investigations are warranted to elucidate roles of host- and drug-induced airway plasma exudation in restriction of viral infection and, specifically, whether it contributes to variable disease responses following exposure to SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , Immunity, Humoral , Respiratory Mucosa/immunology , Respiratory Mucosa/virology , SARS-CoV-2/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Biomarkers/blood , Blood Proteins , COVID-19/diagnosis , COVID-19/metabolism , Capillary Permeability/immunology , Complement Activation/immunology , Complement System Proteins/immunology , Complement System Proteins/metabolism , Exudates and Transudates , Humans , Immunity, Innate , Immunoglobulin M/blood , Immunoglobulin M/immunology , Microvessels/immunology , Microvessels/metabolism , Respiratory Mucosa/metabolism
17.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1084274

ABSTRACT

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Subject(s)
Brain/virology , COVID-19/virology , Induced Pluripotent Stem Cells/virology , Lung/virology , Neural Stem Cells/virology , Organoids/virology , SARS-CoV-2/pathogenicity , Apoptosis/physiology , Brain/metabolism , COVID-19/metabolism , Cells, Cultured , Complement System Proteins/metabolism , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/metabolism , Inflammation/metabolism , Inflammation/virology , Lung/metabolism , Neural Stem Cells/metabolism , Neurons/metabolism , Neurons/virology , Organoids/metabolism , Serine Endopeptidases/metabolism , Signal Transduction/physiology , Stem Cells/metabolism , Stem Cells/virology
18.
Front Immunol ; 11: 599417, 2020.
Article in English | MEDLINE | ID: covidwho-1000095

ABSTRACT

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.


Subject(s)
Complement C5a/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Complement Membrane Attack Complex/antagonists & inhibitors , Kidney Diseases/drug therapy , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Complement Activation/immunology , Complement System Proteins/metabolism , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Humans , Kidney/pathology , Kidney Diseases/immunology , Kidney Diseases/pathology , Lupus Nephritis/drug therapy , Lupus Nephritis/pathology
19.
Cell Biol Int ; 45(4): 702-707, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-985972

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger a cytokine storm in the pulmonary tissue by releasing various types of mediators, leading to acute respiratory distress syndrome (ARDS). Increased neutrophil-to-lymphocyte ratio, as well as CD4+ T lymphopenia, is reported in cases with novel coronavirus disease (COVID-19), meanwhile, lymphopenia is a significant finding in the majority of COVID-19 cases with a severe phenotype. Moreover, excessive activation of monocyte/macrophage and cytokine storms are associated with the severity of the disease and the related complications in SARS-CoV-2 infection. Understanding the immune response dysregulation in COVID-19 is essential to develop more effective diagnostic, therapeutic, and prophylactic strategies in this pandemic.


Subject(s)
COVID-19/pathology , Immunity , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Complement System Proteins/metabolism , Cytokine Release Syndrome/etiology , Humans , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism
20.
Trends Immunol ; 42(2): 94-103, 2021 02.
Article in English | MEDLINE | ID: covidwho-972553

ABSTRACT

Complement is integral to a healthy functioning immune system and orchestrates various innate and adaptive responses against viruses and other pathogens. Despite its importance, the potential beneficial role of complement in immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been overshadowed by reports of extensive complement activation in severe coronavirus disease 2019 (COVID-19) patients. Here, we hypothesize that complement may also have a protective role and could function to enhance virus neutralization by antibodies, promote virus phagocytosis by immune cells, and lysis of virus. These functions might be exploited in the development of effective therapeutics and vaccines against SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Adaptive Immunity , Animals , Antibodies, Viral/metabolism , Complement Activation , Complement System Proteins/metabolism , Humans , Immunity, Innate
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