Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 31
Filter
1.
Front Immunol ; 13: 815833, 2022.
Article in English | MEDLINE | ID: covidwho-1731775

ABSTRACT

The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus may vary from asymptomatic to severe infection with multi-organ failure and death. Increased levels of circulating complement biomarkers have been implicated in COVID-19-related hyperinflammation and coagulopathy. We characterized systemic complement activation at a cellular level in 49-patients with COVID-19. We found increases of the classical complement sentinel C1q and the downstream C3 component on circulating blood monocytes from COVID-19 patients when compared to healthy controls (HCs). Interestingly, the cell surface-bound complement inhibitor CD55 was also upregulated in COVID-19 patient monocytes in comparison with HC cells. Monocyte membrane-bound C1q, C3 and CD55 levels were associated with plasma inflammatory markers such as CRP and serum amyloid A during acute infection. Membrane-bounds C1q and C3 remained elevated even after a short recovery period. These results highlight systemic monocyte-associated complement activation over a broad range of COVID-19 disease severities, with a compensatory upregulation of CD55. Further evaluation of complement and its interaction with myeloid cells at the membrane level could improve understanding of its role in COVID-19 pathogenesis.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Complement System Proteins/immunology , Monocytes/immunology , Adult , Biomarkers/blood , COVID-19/blood , COVID-19/virology , Complement Inactivating Agents/immunology , Cytokines/immunology , Female , Humans , Immunologic Factors/immunology , Male , Middle Aged , Monocytes/virology , SARS-CoV-2/immunology
2.
Viruses ; 13(12)2021 11 26.
Article in English | MEDLINE | ID: covidwho-1542798

ABSTRACT

Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 106 neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 106 neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Inflammation/immunology , Aged , Aged, 80 and over , COVID-19/mortality , Complement C5a , Cytokines/blood , Epithelial Cells , Female , Humans , Inflammation/blood , Kinetics , Longitudinal Studies , Male , Prospective Studies , SARS-CoV-2 , Thorax/diagnostic imaging , Viral Load
3.
Front Immunol ; 12: 716361, 2021.
Article in English | MEDLINE | ID: covidwho-1399137

ABSTRACT

Background: COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective: This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods: Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 µg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results: Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion: Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Inflammation/immunology , Neoplasms/immunology , SARS-CoV-2/immunology , Thrombosis/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/virology , Complement Inactivating Agents/blood , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Inflammation/blood , Male , Middle Aged , Neoplasms/blood , Platelet Activation/immunology , Retrospective Studies , SARS-CoV-2/physiology , Thrombosis/blood , Young Adult
4.
Front Immunol ; 12: 716075, 2021.
Article in English | MEDLINE | ID: covidwho-1359192

ABSTRACT

The existence of asymptomatic and re-detectable positive coronavirus disease 2019 (COVID-19) patients presents the disease control challenges of COVID-19. Most studies on immune responses in COVID-19 have focused on moderately or severely symptomatic patients; however, little is known about the immune response in asymptomatic and re-detectable positive (RP) patients. Here we performed a comprehensive analysis of the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from 48 COVID-19 patients which included 8 asymptomatic, 13 symptomatic, 15 recovered and 12 RP patients. The weighted gene co-expression network analysis (WGCNA) identified six co-expression modules, of which the turquoise module was positively correlated with the asymptomatic, symptomatic, and recovered COVID-19 patients. The red module positively correlated with symptomatic patients only and the blue and brown modules positively correlated with the RP patients. The analysis by single sample gene set enrichment analysis (ssGSEA) revealed a lower level of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, gene set enrichment analysis (GSEA) analysis showed the enrichment of TNFα/NF-κB and influenza infection in the RP patients compared with the recovered patients, indicating a hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression of COVID-19 disease and assist clinical management and the immunotherapy development for COVID-19.


Subject(s)
Asymptomatic Diseases , COVID-19/immunology , Carrier State/immunology , Leukocytes, Mononuclear/immunology , SARS-CoV-2/immunology , Transcriptome/genetics , Adult , Carrier State/virology , Complement Activation/immunology , Female , Gene Expression Profiling , Humans , Inflammation/immunology , Influenza, Human/complications , Interferons/blood , Interferons/immunology , Male , Middle Aged , NF-kappa B/metabolism , Transcriptome/immunology , Tumor Necrosis Factor-alpha/metabolism , Young Adult
5.
Viruses ; 13(5)2021 05 02.
Article in English | MEDLINE | ID: covidwho-1251799

ABSTRACT

The complement system represents a crucial part of innate immunity. It contains a diverse range of soluble activators, membrane-bound receptors, and regulators. Its principal function is to eliminate pathogens via activation of three distinct pathways: classical, alternative, and lectin. In the case of viruses, the complement activation results in effector functions such as virion opsonisation by complement components, phagocytosis induction, virolysis by the membrane attack complex, and promotion of immune responses through anaphylatoxins and chemotactic factors. Recent studies have shown that the addition of individual complement components can neutralise viruses without requiring the activation of the complement cascade. While the complement-mediated effector functions can neutralise a diverse range of viruses, numerous viruses have evolved mechanisms to subvert complement recognition/activation by encoding several proteins that inhibit the complement system, contributing to viral survival and pathogenesis. This review focuses on these complement-dependent and -independent interactions of complement components (especially C1q, C4b-binding protein, properdin, factor H, Mannose-binding lectin, and Ficolins) with several viruses and their consequences.


Subject(s)
Complement Activation/immunology , Complement System Proteins/immunology , Immunity, Innate , Receptors, Pattern Recognition/immunology , Viruses/immunology , Complement System Proteins/genetics , Cytokine Release Syndrome , Cytopathogenic Effect, Viral , Humans
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.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L485-L489, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1299247

ABSTRACT

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.


Subject(s)
COVID-19/complications , Complement Activation/immunology , Complement C3b/immunology , Complement C4b/immunology , Erythrocytes/immunology , Peptide Fragments/immunology , Respiratory Insufficiency/diagnosis , Sepsis/diagnosis , COVID-19/immunology , COVID-19/virology , Complement C3b/metabolism , Complement C4b/metabolism , Erythrocytes/metabolism , Erythrocytes/virology , Female , Humans , Male , Middle Aged , Peptide Fragments/metabolism , Respiratory Insufficiency/immunology , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/virology , SARS-CoV-2/isolation & purification , Sepsis/immunology , Sepsis/metabolism , Sepsis/virology
8.
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
9.
Mol Cell Biochem ; 476(10): 3815-3825, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1263168

ABSTRACT

Chagas and COVID-19 are diseases caused by Trypanosoma cruzi and SARS-CoV-2, respectively. These diseases present very different etiological agents despite showing similarities such as susceptibility/risk factors, pathogen-associated molecular patterns (PAMPs), recognition of glycosaminoglycans, inflammation, vascular leakage hypercoagulability, microthrombosis, and endotheliopathy; all of which suggest, in part, treatments with similar principles. Here, both diseases are compared, focusing mainly on the characteristics related to dysregulated immunothrombosis. Given the in-depth investigation of molecules and mechanisms related to microthrombosis in COVID-19, it is necessary to reconsider a prompt treatment of Chagas disease with oral anticoagulants.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/pathology , Chagas Disease/pathology , Heparitin Sulfate/therapeutic use , Thrombosis/drug therapy , Thrombosis/pathology , Blood Platelets/immunology , COVID-19/immunology , Chagas Disease/immunology , Complement Activation/immunology , Endothelium/pathology , Humans , Pathogen-Associated Molecular Pattern Molecules/immunology , Platelet Activation/immunology , SARS-CoV-2/immunology , Trypanosoma cruzi/immunology
10.
Int Rev Immunol ; 40(1-2): 54-71, 2021.
Article in English | MEDLINE | ID: covidwho-1236149

ABSTRACT

Lack of standardized therapeutic approaches is arguably the significant contributor to the high burden of mortality observed in the ongoing pandemic of the Coronavirus disease, 2019 (COVID-19). Evidence is accumulating on SARS-CoV-2 specific immune cell dysregulation and consequent tissue injury in COVID-19. Currently, no definite drugs or vaccines are available against the disease; however initial results of the ongoing clinical trials have raised some hope. In this article, taking insights from the emerging empirical evidence about host-virus interactions, we deliberate upon plausible pathogenic mechanisms and suitable therapeutic approaches for COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate/immunology , SARS-CoV-2/immunology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Complement Activation/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Host-Pathogen Interactions/immunology , Humans , SARS-CoV-2/drug effects
13.
J Cutan Pathol ; 48(9): 1166-1172, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1208906

ABSTRACT

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID-19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID-19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS-CoV-2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID-19.


Subject(s)
Buttocks/pathology , COVID-19/complications , COVID-19/pathology , Purpura/diagnosis , Sacrum/pathology , Aged , Anticoagulants/therapeutic use , Biopsy/methods , Buttocks/virology , COVID-19/diagnosis , COVID-19/immunology , Calciphylaxis/diagnosis , Complement Activation/immunology , Diagnosis, Differential , Disease Progression , Fatal Outcome , Female , Humans , Inpatients , Platelet Aggregation/immunology , Purpura/virology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sacrum/virology , Skin/pathology , Skin Diseases, Vascular/etiology , Skin Diseases, Vascular/pathology
14.
Front Immunol ; 12: 663187, 2021.
Article in English | MEDLINE | ID: covidwho-1177984

ABSTRACT

Objectives: Uncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19. Methods: In this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records. Results: Increased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55-8.45, 95% CI) and 6.1 (2.1-17.8), respectively]. Conclusion: Increased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Complement Activation/immunology , Complement C3a/immunology , Hospital Mortality , SARS-CoV-2/immunology , Adult , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Survival Rate
16.
Clin Immunol ; 226: 108716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1152310

ABSTRACT

Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , Complement Pathway, Alternative/immunology , Lung Injury/immunology , Aged , Aged, 80 and over , COVID-19/complications , Complement Inactivating Agents/pharmacology , Complement Inactivating Agents/therapeutic use , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Immunohistochemistry , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung Injury/complications , Lung Injury/pathology , Lung Injury/virology , Male , Middle Aged
17.
Eur J Immunol ; 51(7): 1652-1659, 2021 07.
Article in English | MEDLINE | ID: covidwho-1141308

ABSTRACT

The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.


Subject(s)
COVID-19/pathology , Complement C5a/antagonists & inhibitors , Cytokine Release Syndrome/pathology , Cytokines/immunology , Immunotherapy/methods , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , COVID-19/drug therapy , COVID-19/immunology , Complement Activation/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/immunology , Signal Transduction/immunology , Thrombosis/immunology , Thrombosis/pathology
18.
Elife ; 102021 03 16.
Article in English | MEDLINE | ID: covidwho-1136623

ABSTRACT

COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , SARS-CoV-2 , Seroconversion , Biomarkers , COVID-19/immunology , COVID-19/metabolism , Comorbidity , Complement Activation/immunology , Complement System Proteins/immunology , Hematopoiesis , Homeostasis , Hospitalization , Humans , Hypoalbuminemia , Interferons/metabolism , Models, Biological , Seroepidemiologic Studies , Signal Transduction
19.
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
20.
J Infect Dis ; 223(2): 214-224, 2021 02 03.
Article in English | MEDLINE | ID: covidwho-1081282

ABSTRACT

BACKGROUND: Excessive activation of immune responses in coronavirus disease 2019 (COVID-19) is considered to be related to disease severity, complications, and mortality rate. The complement system is an important component of innate immunity and can stimulate inflammation, but its role in COVID-19 is unknown. METHODS: A prospective, longitudinal, single center study was performed in hospitalized patients with COVID-19. Plasma concentrations of complement factors C3a, C3c, and terminal complement complex (TCC) were assessed at baseline and during hospital admission. In parallel, routine laboratory and clinical parameters were collected from medical files and analyzed. RESULTS: Complement factors C3a, C3c, and TCC were significantly increased in plasma of patients with COVID-19 compared with healthy controls (P < .05). These complement factors were especially elevated in intensive care unit patients during the entire disease course (P < .005 for C3a and TCC). More intense complement activation was observed in patients who died and in those with thromboembolic events. CONCLUSIONS: Patients with COVID-19 demonstrate activation of the complement system, which is related to disease severity. This pathway may be involved in the dysregulated proinflammatory response associated with increased mortality rate and thromboembolic complications. Components of the complement system might have potential as prognostic markers for disease severity and as therapeutic targets in COVID-19.


Subject(s)
COVID-19/immunology , Complement Activation/immunology , SARS-CoV-2/immunology , Aged , Aged, 80 and over , COVID-19/mortality , Complement C3c/immunology , Cytokines/blood , Disease Progression , Female , Humans , Immunity, Innate , Inflammation/immunology , Longitudinal Studies , Male , Middle Aged , Mortality , Netherlands/epidemiology , Prospective Studies , Respiratory Distress Syndrome/immunology , Severity of Illness Index
SELECTION OF CITATIONS
SEARCH DETAIL