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1.
J Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
2.
J Clin Invest ; 130(11): 6151-6157, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1435146

ABSTRACT

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.


Subject(s)
Betacoronavirus , Complement Membrane Attack Complex , Coronavirus Infections , Extracellular Traps , Neutrophils , Pandemics , Pneumonia, Viral , Thromboplastin , Thrombosis , Aged , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Complement Activation/drug effects , Complement Membrane Attack Complex/immunology , Complement Membrane Attack Complex/metabolism , Coronavirus Infections/blood , Coronavirus Infections/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Peptides, Cyclic/pharmacology , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Receptor, Anaphylatoxin C5a/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombin/immunology , Thrombin/metabolism , Thromboplastin/immunology , Thromboplastin/metabolism , Thrombosis/blood , Thrombosis/immunology , Thrombosis/virology
3.
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
4.
Medicine (Baltimore) ; 100(20): e25456, 2021 May 21.
Article in English | MEDLINE | ID: covidwho-1324829

ABSTRACT

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hemopoietic stem cell disorder characterized by the triad of hemolytic anemia, thrombosis, and impaired bone marrow function. Evidence suggests that severe outcomes in COVID19 infection are attributed to the excessive activation of the complement cascade leading to acute lung injury and associated is with an increased prothrombotic state. PATIENT CONCERNS: A 27-year-old Caucasian man with PNH presented to the Emergency Department of our hospital with acute onset shortness of breath, cough and blood in urine. DIAGNOSIS: The patient was diagnosed with acute hemolytic exacerbation of PNH complicated with moderate COVID19 pneumonia. OUTCOMES: The patient was initiated with an anticoagulant unfractionated heparin, dexamethasone, and cefuroxime injection. His symptoms quickly resolved, and he was discharged after 5 days. CONCLUSION: The complement system activation is a critical component in the sequalae of COVID19 infection. Evidence suggests that severe outcomes in COVID19 infection are attributed to the excessive activation of the complement cascade leading to acute lung injury and associated is with an increased prothrombotic state. Notably, C5a concentration was noted to be higher in patients with COVID19 infection. The use of complement inhibitors to attenuate immune mediated damage in COVID19 nevertheless represents a very interesting theoretical approach. However, careful consideration as to which patients may benefit will be required and the outcome of clinical trials needed.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Complement Inactivating Agents/administration & dosage , Hemoglobinuria, Paroxysmal/complications , Thrombosis/prevention & control , Adult , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , COVID-19 Serological Testing , Complement Activation/drug effects , Hemoglobinuria, Paroxysmal/blood , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/immunology , Humans , Male , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Symptom Flare Up , Thrombosis/immunology , Treatment Outcome
5.
Adv Drug Deliv Rev ; 178: 113848, 2021 11.
Article in English | MEDLINE | ID: covidwho-1283843

ABSTRACT

The emergence of SARS-CoV-2, and the ensuing global pandemic, has resulted in an unprecedented response to identify therapies that can limit uncontrolled inflammation observed in patients with moderate to severe COVID-19. The immune pathology behind COVID-19 is complex and involves the activation and interaction of multiple systems including, but not limited to, complement, inflammasomes, endothelial as well as innate and adaptive immune cells to bring about a convoluted profile of inflammation, coagulation and tissue damage. To date, therapeutic approaches have focussed on inhibition of coagulation, untargeted immune suppression and/or cytokine-directed blocking agents. Regardless of recently achieved improvements in individual patient outcomes and survival rates, improved and focussed approaches targeting individual systems involved is needed to further improve prognosis and wellbeing. This review summarizes the current understanding of molecular and cellular systems involved in the pathophysiology of COVID-19, and their contribution to pathogen clearance and damage to then discuss possible therapeutic options involving immunomodulatory drug delivery systems as well as summarising the complex interplay between them.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Drug Delivery Systems/methods , Immunologic Factors/administration & dosage , Inflammasomes/antagonists & inhibitors , Adjuvants, Immunologic/administration & dosage , Animals , Antiviral Agents/immunology , COVID-19/immunology , Communicable Diseases/drug therapy , Communicable Diseases/immunology , Complement Activation/drug effects , Complement Activation/immunology , Drug Delivery Systems/trends , Humans , Immunologic Factors/immunology , Inflammasomes/immunology
6.
Nat Commun ; 12(1): 2697, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225508

ABSTRACT

Although human antibodies elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-reactive antibodies. Herein, we isolate and profile a panel of 32 N protein-specific monoclonal antibodies (mAbs) from a quick recovery coronavirus disease-19 (COVID-19) convalescent patient who has dominant antibody responses to the SARS-CoV-2 N protein rather than to the SARS-CoV-2 spike (S) protein. The complex structure of the N protein RNA binding domain with the highest binding affinity mAb (nCoV396) reveals changes in the epitopes and antigen's allosteric regulation. Functionally, a virus-free complement hyperactivation analysis demonstrates that nCoV396 specifically compromises the N protein-induced complement hyperactivation, which is a risk factor for the morbidity and mortality of COVID-19 patients, thus laying the foundation for the identification of functional anti-N protein mAbs.


Subject(s)
Antibodies, Viral/pharmacology , COVID-19/immunology , Complement Activation/drug effects , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Allosteric Regulation , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibody Affinity , Antigen-Antibody Complex/chemistry , Convalescence , Coronavirus Nucleocapsid Proteins/chemistry , Crystallography, X-Ray , Epitopes , Humans , Phosphoproteins/chemistry , Phosphoproteins/immunology , Protein Conformation
10.
Life Sci ; 272: 119245, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1087130

ABSTRACT

In the past 20 years, infections caused by coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 have posed a threat to public health since they may cause severe acute respiratory syndrome (SARS) in humans. The Complement System is activated during viral infection, being a central protagonist of innate and acquired immunity. Here, we report some interactions between these three coronaviruses and the Complement System, highlighting the central role of C3 with the severity of these infections. Although it can be protective, its role during coronavirus infections seems to be contradictory. For example, during SARS-CoV-2 infection, Complement System can control the viral infection in asymptomatic or mild cases; however, it can also intensify local and systemic damage in some of severe COVID-19 patients, due to its potent proinflammatory effect. In this last condition, the activation of the Complement System also amplifies the cytokine storm and the pathogenicity of coronavirus infection. Experimental treatment with Complement inhibitors has been an enthusiastic field of intense investigation in search of a promising additional therapy in severe COVID-19 patients.


Subject(s)
COVID-19/immunology , Complement System Proteins/immunology , SARS-CoV-2/immunology , Animals , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Complement Activation/drug effects , Complement C3/immunology , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology
11.
Hum Immunol ; 82(4): 264-269, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1039363

ABSTRACT

The novel Coronavirus SARS-CoV-2 is the viral pathogen responsible for the ongoing global pandemic, COVID-19 (Coronavirus disease 2019). To date, the data recorded indicate 1.62 Mln deaths and 72.8 Mln people infected (WHO situation report Dec 2020). On December 27, the first anti-COVID-19 vaccinations started in Europe. There are no direct antivirals against SARS-CoV-2. Understanding the pathophysiological and inflammatory/immunological processes of SARS-CoV-2 infection is essential to identify new drug therapies. In the most severe COVID-19 cases, an unregulated immunological/inflammatory system results in organ injury that can be fatal to the host in some cases. Pharmacologic approaches to normalize the unregulated inflammatory/immunologic response is an important therapeutic solution. Evidence associates a non-regulation of the "complement system" as one of the causes of generalized inflammation causing multi-organ dysfunction. Serum levels of a complement cascade mediator, factor "C5a", have been found in high concentrations in the blood of COVID-19 patients with severe disease. In this article we discuss the correlation between complement system and COVID-19 infection and pharmacological solutions directed to regulate.


Subject(s)
COVID-19/drug therapy , Complement Activation/drug effects , Complement C3a/antagonists & inhibitors , Complement C5a/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/pathology , COVID-19/physiopathology , Complement Activation/immunology , Complement C3a/immunology , Complement C5a/immunology , Humans , SARS-CoV-2/immunology
13.
Clin Immunol ; 220: 108598, 2020 11.
Article in English | MEDLINE | ID: covidwho-778645

ABSTRACT

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Subject(s)
Betacoronavirus/pathogenicity , Complement C3/antagonists & inhibitors , Complement C5/antagonists & inhibitors , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Cohort Studies , Complement Activation/drug effects , Complement C3/genetics , Complement C3/immunology , Complement C5/genetics , Complement C5/immunology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Extracellular Traps/drug effects , Female , Gene Expression , Humans , Interleukin-6/metabolism , Male , Middle Aged , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/virology , Pandemics , Peptides, Cyclic/therapeutic use , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Severity of Illness Index
14.
J Clin Invest ; 130(11): 5674-5676, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-760323

ABSTRACT

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19-induced inflammation.


Subject(s)
Betacoronavirus/metabolism , Complement Activation/drug effects , Coronavirus Infections , Pandemics , Peptides, Cyclic/pharmacology , Pneumonia, Viral , Thromboplastin/biosynthesis , Thrombotic Microangiopathies , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Neutrophils/metabolism , Neutrophils/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , SARS-CoV-2 , Severity of Illness Index , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/metabolism , Thrombotic Microangiopathies/pathology , Thrombotic Microangiopathies/virology
15.
Blood ; 136(18): 2080-2089, 2020 10 29.
Article in English | MEDLINE | ID: covidwho-740364

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.


Subject(s)
Betacoronavirus , Complement Factor D/antagonists & inhibitors , Complement Inactivating Agents/pharmacology , Complement Pathway, Alternative/drug effects , Spike Glycoprotein, Coronavirus/pharmacology , Cell Line , Complement Activation/drug effects , Complement C3/metabolism , Complement C5/antagonists & inhibitors , Complement Factor H/metabolism , Complement Membrane Attack Complex/metabolism , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/physiology
16.
J Thromb Haemost ; 18(11): 2812-2822, 2020 11.
Article in English | MEDLINE | ID: covidwho-697181

ABSTRACT

In December 2019, the world was introduced to a new betacoronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for its propensity to cause rapidly progressive lung damage, resulting in high death rates. As fast as the virus spread, it became evident that the novel coronavirus causes a multisystem disease (COVID-19) that may involve multiple organs and has a high risk of thrombosis associated with striking elevations in pro-inflammatory cytokines, D-dimer, and fibrinogen, but without disseminated intravascular coagulation. Postmortem studies have confirmed the high incidence of venous thromboembolism, but also notably revealed diffuse microvascular thrombi with endothelial swelling, consistent with a thrombotic microangiopathy, and inter-alveolar endothelial deposits of complement activation fragments. The clinicopathologic presentation of COVID-19 thus parallels that of other thrombotic diseases, such as atypical hemolytic uremic syndrome (aHUS), that are caused by dysregulation of the complement system. This raises the specter that many of the thrombotic complications arising from SARS-CoV-2 infections may be triggered and/or exacerbated by excess complement activation. This is of major potential clinical relevance, as currently available anti-complement therapies that are highly effective in protecting against thrombosis in aHUS, could be efficacious in COVID-19. In this review, we provide mounting evidence for complement participating in the pathophysiology underlying the thrombotic diathesis associated with pathogenic coronaviruses, including SARS-CoV-2. Based on current knowledge of complement, coagulation and the virus, we suggest lines of study to identify novel therapeutic targets and the rationale for clinical trials with currently available anti-complement agents for COVID-19.


Subject(s)
Blood Coagulation , COVID-19/immunology , Complement Activation , Complement System Proteins/immunology , SARS-CoV-2/immunology , Thrombosis/immunology , Animals , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/drug therapy , COVID-19/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Host-Pathogen Interactions , Humans , Thrombosis/blood , Thrombosis/prevention & control , Thrombosis/virology
17.
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
19.
J Immunol ; 205(6): 1488-1495, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-662455

ABSTRACT

Coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory infection that is caused by the severe acute respiratory syndrome coronavirus 2. Although most people are immunocompetent to the virus, a small group fail to mount an effective antiviral response and develop chronic infections that trigger hyperinflammation. This results in major complications, including acute respiratory distress syndrome, disseminated intravascular coagulation, and multiorgan failure, which all carry poor prognoses. Emerging evidence suggests that the complement system plays a key role in this inflammatory reaction. Indeed, patients with severe COVID-19 show prominent complement activation in their lung, skin, and sera, and those individuals who were treated with complement inhibitors all recovered with no adverse reactions. These and other studies hint at complement's therapeutic potential in these sequalae, and thus, to support drug development, in this review, we provide a summary of COVID-19 and review complement's role in COVID-19 acute respiratory distress syndrome and coagulopathy.


Subject(s)
Blood Coagulation Disorders/virology , Complement Activation/physiology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Respiratory Distress Syndrome/virology , Animals , Betacoronavirus/immunology , Blood Coagulation/drug effects , Blood Coagulation Disorders/immunology , COVID-19 , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Complement System Proteins/drug effects , Coronavirus Infections/blood , Coronavirus Infections/immunology , Humans , Inflammation/immunology , Inflammation/virology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , SARS-CoV-2
20.
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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