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Front Immunol ; 13: 946522, 2022.
Article in English | MEDLINE | ID: covidwho-2022727


Numerous publications have underlined the link between complement C5a and the clinical course of COVID-19. We previously reported that levels of C5a remain high in the group of severely ill patients up to 90 days after hospital discharge. We have now evaluated which complement pathway fuels the elevated levels of C5a during hospitalization and follow-up. The alternative pathway (AP) activation marker C3bBbP and the soluble fraction of C4d, a footprint of the classical/lectin (CP/LP) pathway, were assessed by immunoenzymatic assay in a total of 188 serial samples from 49 patients infected with SARS-CoV-2. Unlike C5a, neither C3bBbP nor C4d readouts rose proportionally to the severity of the disease. Detailed correlation analyses in hospitalization and follow-up samples collected from patients of different disease severity showed significant positive correlations of AP and CP/LP markers with C5a in certain groups, except for the follow-up samples of the patients who suffered from highly severe COVID-19 and presented the highest C5a readouts. In conclusion, there is not a clear link between persistently high levels of C5a after hospital discharge and markers of upstream complement activation, suggesting the existence of a non-canonical source of C5a in patients with a severe course of COVID-19.

COVID-19 , Complement Activation , Complement C3b , Complement C4b , Complement C5a , Complement Factor B , Peptide Fragments , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , Complement Activation/immunology , Complement C3b/immunology , Complement C4b/immunology , Complement C5a/analysis , Complement C5a/immunology , Complement Factor B/immunology , Complement System Proteins/immunology , Humans , Peptide Fragments/immunology , SARS-CoV-2
Nat Immunol ; 23(1): 62-74, 2022 01.
Article in English | MEDLINE | ID: covidwho-1514418


The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.

Interferon-gamma/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Vitamin D/metabolism , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Bronchoalveolar Lavage Fluid/cytology , COVID-19/immunology , COVID-19/pathology , Complement C3a/immunology , Complement C3b/immunology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Lymphocyte Activation/immunology , Receptors, Calcitriol/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunology , Transcription, Genetic/genetics
Am J Physiol Lung Cell Mol Physiol ; 321(2): L485-L489, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1299247


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.

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