RESUMEN
To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2, we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase, and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus, suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies.
Asunto(s)
COVID-19/inmunología , COVID-19/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , SARS-CoV-2 , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Citocinas/sangre , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Femenino , Glucógeno Fosforilasa de Forma Hepática/sangre , Granulocitos/inmunología , Granulocitos/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/sangre , Masculino , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/inmunología , Persona de Mediana Edad , Activación Neutrófila , Peroxidasa/sangre , Estallido Respiratorio , Índice de Severidad de la EnfermedadAsunto(s)
COVID-19/inmunología , ADN/sangre , Trampas Extracelulares , Peroxidasa/sangre , SARS-CoV-2 , Adulto , Biomarcadores/sangre , Femenino , Histonas/sangre , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Immune homeostasis is disturbed during severe viral infections, which can lead to loss of tolerance to self-peptides and result in short- or long-term autoimmunity. Using publicly available transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression levels of 52 autoantigens, known to be associated with 24 autoimmune diseases, during SAR-CoV-2 infection. Seven autoantigens (MPO, PRTN3, PADI4, IFIH1, TRIM21, PTPRN2, and TSHR) were upregulated in whole blood samples. MPO and TSHR were overexpressed in both lung autopsies and whole blood tissue and were associated with more severe COVID-19. Neutrophil activation derived autoantigens (MPO, PRTN3, and PADI4) were prominently increased in blood of both SARS-CoV-1 and SARS-CoV-2 viral infections, while TSHR and PTPRN2 autoantigens were specifically increased in SARS-CoV-2. Using single-cell dataset from peripheral blood mononuclear cells (PBMCs), we observed an upregulation of MPO, PRTN3, and PADI4 autoantigens within the low-density neutrophil subset. To validate our in-silico analysis, we measured plasma protein levels of two autoantigens, MPO and PRTN3, in severe and asymptomatic COVID-19. The protein levels of these two autoantigens were significantly upregulated in more severe COVID-19 infections. In conclusion, the immunopathology and severity of COVID-19 could result in transient autoimmune activation. Longitudinal follow-up studies of confirmed cases of COVID-19 could determine the enduring effects of viral infection including development of autoimmune disease.
Asunto(s)
Autoantígenos/genética , Autoinmunidad/genética , COVID-19/inmunología , SARS-CoV-2/inmunología , Transcriptoma , Enfermedades Asintomáticas , Autoantígenos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , COVID-19/sangre , COVID-19/patología , COVID-19/virología , Simulación por Computador , Bases de Datos Genéticas , Humanos , Pulmón/patología , Mieloblastina/sangre , Mieloblastina/genética , Activación Neutrófila , Neutrófilos/inmunología , Peroxidasa/sangre , Peroxidasa/genética , RNA-Seq , Índice de Severidad de la Enfermedad , Regulación hacia Arriba/genéticaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.