Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
1.
J Endocrinol Invest ; 45(5): 1021-1029, 2022 May.
Artículo en Inglés | MEDLINE | ID: covidwho-1783035

RESUMEN

OBJECTIVE: Obesity is a recognized risk factor for the progression to severe forms of COVID-19, yet the mechanisms of the association are unclear. METHODS: Subcutaneous abdominal adipose tissue specimens of subjects deceased from COVID-19 (n = 23) were compared to those of controls dying abruptly from causes other than infectious (accidental trauma, sudden cardiac death). Alterations of lung parenchyma consistent with moderate to severe disease were detected in all COVID-19 cases, not in controls. Investigations included: histopathologic features, detection of virus antigens and genome, characterization of infiltrating leukocytes, transcription levels of immune-related genes. RESULTS: By RT-PCR, the SARS-CoV-2 genome was detected in the adipose tissue of 13/23 (56%) cases of the COVID-19 cohort. The virus nucleocapsid antigen was detected in the cytoplasm of 1-5% adipocytes in 12/12 COVID-19 cases that were virus-positive by PCR in the adipose tissue (one case could not be assessed due insufficient tissue). The adipose tissue of COVID-19 cases showed leukocyte infiltrates and upregulation of the interferon-alpha pathway. After adjusting for age and sex, the activation score of IFN-alpha was directly related with transcription levels of the ACE2 gene, a key entry factor of SARS-CoV-2. CONCLUSIONS: In lethal COVID-19 cases, the SARS-CoV-2 nucleocapsid antigen has been detected in a sizeable proportion of adipocytes, showing that the virus may directly infect the parenchymal cells of subcutaneous fat. Infection appears to activate the IFN alpha pathway and to attract infiltrating leukocytes. Due to the huge numbers of adipocytes in adults, the adipose tissue represents a significant reservoir for SARS-CoV-2 and an important source of inflammatory mediators.


Asunto(s)
Adipocitos , Tejido Adiposo , COVID-19 , Interferón-alfa , SARS-CoV-2 , Adipocitos/inmunología , Tejido Adiposo/inmunología , Adulto , COVID-19/diagnóstico , COVID-19/inmunología , COVID-19/virología , Humanos , Interferón-alfa/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación
2.
EMBO J ; 41(10): e109622, 2022 05 16.
Artículo en Inglés | MEDLINE | ID: covidwho-1700141

RESUMEN

Understanding the molecular pathways driving the acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments for severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion is transient and coincides with decreased expression of antiviral type I IFNα and of systemic inflammatory cytokines CXCL10 and IL-6. Using an in vitro stem cell-based human pDC model, we further demonstrate that pDCs, while not supporting SARS-CoV-2 replication, directly sense the virus and in response produce multiple antiviral (interferons: IFNα and IFNλ1) and inflammatory (IL-6, IL-8, CXCL10) cytokines that protect epithelial cells from de novo SARS-CoV-2 infection. Via targeted deletion of virus-recognition innate immune pathways, we identify TLR7-MyD88 signaling as crucial for production of antiviral interferons (IFNs), whereas Toll-like receptor (TLR)2 is responsible for the inflammatory IL-6 response. We further show that SARS-CoV-2 engages the receptor neuropilin-1 on pDCs to selectively mitigate the antiviral interferon response, but not the IL-6 response, suggesting neuropilin-1 as potential therapeutic target for stimulation of TLR7-mediated antiviral protection.


Asunto(s)
COVID-19 , Células Dendríticas , Receptor Toll-Like 2 , Receptor Toll-Like 7 , COVID-19/inmunología , COVID-19/patología , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/patología , Humanos , Interferón Tipo I/inmunología , Interferón-alfa/inmunología , Interleucina-6/inmunología , Neuropilina-1/inmunología , SARS-CoV-2 , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 7/inmunología
3.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artículo en Inglés | MEDLINE | ID: covidwho-1671749

RESUMEN

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2-infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Interferón-alfa/farmacología , SARS-CoV-2/efectos de los fármacos , Transcriptoma , Replicación Viral/efectos de los fármacos , Animales , COVID-19/inmunología , COVID-19/virología , Chlorocebus aethiops , Clonación Molecular , Modelos Animales de Enfermedad , Escherichia coli/genética , Escherichia coli/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Ratones , Isoformas de Proteínas/clasificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/farmacología , Proteínas Recombinantes/clasificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Transducción de Señal , Células Vero
4.
Int Immunopharmacol ; 101(Pt B): 108254, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: covidwho-1549846

RESUMEN

With the outbreak and rapid spread of COVID-19, the world health situation is unprecedentedly severe. Systemic lupus erythematosus (SLE) is a common autoimmune disease, which can cause multiple organ damage. Numerous studies have shown that immune factors have important roles in the pathogenesis of both COVID-19 and SLE. In the early stages of COVID-19 and SLE pathogenesis, IFN-α expression is frequently increased, which aggravates the virus infection and promotes SLE development. In addition, increased IL-6 levels, caused by different mechanisms, are observed in the peripheral blood of patients with severe COVID-19 and SLE, stimulating a series of immune cascades that lead to a cytokine storm, as well as causing B cell hyperfunction and production of numerous of antibodies, aggravating both COVID-19 and SLE. In this review, we explore the background immunopathological mechanisms in COVID-19 and SLE and analyze the advantages and disadvantages of commonly used SLE drugs for patients with COVID-19, to optimize treatment plans for patients with SLE who develop COVID-19.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Interferón-alfa/inmunología , Interleucina-6/inmunología , Lupus Eritematoso Sistémico/inmunología , SARS-CoV-2 , Animales , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico
5.
Clin Immunol ; 233: 108888, 2021 12.
Artículo en Inglés | MEDLINE | ID: covidwho-1517099

RESUMEN

Human interferon alpha (hIFN-α) administration constitutes the current FDA approved therapy for chronic Hepatitis B and C virus infections. Additionally, hIFN-α treatment efficacy was recently demonstrated in patients with COVID-19. Thus, hIFN-α constitutes a therapeutic alternative for those countries where vaccination is inaccessible and for people who did not respond effectively to vaccination. However, hIFN-α2b exhibits a short plasma half-life resulting in the occurrence of severe side effects. To optimize the cytokine's pharmacokinetic profile, we developed a hyperglycosylated IFN, referred to as GMOP-IFN. Given the significant number of reports showing neutralizing antibodies (NAb) formation after hIFN-α administration, here we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two GMOP-IFN variants exhibited significantly reduced ex vivo immunogenicity and null antiproliferative activity, while preserving antiviral function. The results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy.


Asunto(s)
Hepatitis B Crónica/inmunología , Hepatitis C Crónica/inmunología , Interferón-alfa/inmunología , Proteínas Recombinantes/inmunología , Adulto , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/inmunología , Antivirales/inmunología , Antivirales/farmacología , Células CHO , COVID-19/inmunología , COVID-19/virología , Bovinos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cricetinae , Cricetulus , Estabilidad de Medicamentos , Células HEK293 , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/genética , Interferón-alfa/farmacología , Proteínas Recombinantes/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Tratamiento Farmacológico de COVID-19
6.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: covidwho-1442406

RESUMEN

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Asunto(s)
COVID-19/inmunología , Interferón-alfa/inmunología , Células Asesinas Naturales/inmunología , SARS-CoV-2/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Secuencia de Bases , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Interferón-alfa/sangre , Fibrosis Pulmonar/patología , RNA-Seq , Índice de Severidad de la Enfermedad , Transcriptoma/genética , Reino Unido , Estados Unidos
7.
Sci Immunol ; 6(62)2021 08 19.
Artículo en Inglés | MEDLINE | ID: covidwho-1434875

RESUMEN

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.


Asunto(s)
Autoanticuerpos/inmunología , COVID-19/inmunología , Interferón Tipo I/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/sangre , COVID-19/mortalidad , Estudios de Casos y Controles , Niño , Preescolar , Enfermedad Crítica , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Lactante , Recién Nacido , Interferón-alfa/inmunología , Persona de Mediana Edad , Adulto Joven
8.
Front Immunol ; 12: 718744, 2021.
Artículo en Inglés | MEDLINE | ID: covidwho-1417083

RESUMEN

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1ß, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.


Asunto(s)
COVID-19/patología , Citocinas/sangre , Interferón-alfa/biosíntesis , Interferones/biosíntesis , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adulto , Autoanticuerpos/sangre , Quimiocina CXCL10/biosíntesis , Comorbilidad , Exoma/genética , Femenino , Humanos , Interferón-alfa/inmunología , Interferones/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Secuenciación del Exoma , Adulto Joven , Interferón lambda
9.
Clin Immunol ; 231: 108851, 2021 10.
Artículo en Inglés | MEDLINE | ID: covidwho-1401323

RESUMEN

Almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) have neutralizing antibodies against type 1 interferons (IFN), important mediators of antiviral defense. Recently, neutralizing anti-IFN antibodies were shown to be a risk factor of severe COVID-19. Here we show in a cohort of 44 patients with APS-1 that higher titers of neutralizing anti-IFNα4 antibodies are associated with a higher and earlier incidence of VZV reactivation (herpes zoster). The patients also present with uncommonly severe clinical sequelae of herpetic infections. APS-1 patients had decreased humoral immune responses to varicella zoster virus, but cellular responses were comparable to healthy controls. These results suggest that blocking the type I interferon pathway in patients with APS-1 patients leads to a clinically significant immune deficiency, and susceptibility to herpesviruses should be taken into account when treating patients with APS-1.


Asunto(s)
Herpesvirus Humano 3 , Poliendocrinopatías Autoinmunes/complicaciones , Infección por el Virus de la Varicela-Zóster/complicaciones , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Femenino , Humanos , Inmunidad Celular , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Poliendocrinopatías Autoinmunes/inmunología , Factores de Riesgo , Infección por el Virus de la Varicela-Zóster/patología , Adulto Joven
10.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: covidwho-1392810

RESUMEN

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Microambiente Celular/inmunología , Pulmón/inmunología , Receptores CXCR3/inmunología , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/inmunología , Animales , Linfocitos T CD8-positivos/patología , COVID-19/patología , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/patología , Interferón-alfa/inmunología , Interleucina-6/inmunología , Pulmón/patología , Pulmón/virología , Macaca mulatta , Masculino
11.
Signal Transduct Target Ther ; 5(1): 221, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: covidwho-1387195
12.
Cell Mol Immunol ; 18(9): 2128-2139, 2021 09.
Artículo en Inglés | MEDLINE | ID: covidwho-1320227

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin ß7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.


Asunto(s)
COVID-19/inmunología , Células Dendríticas/inmunología , SARS-CoV-2/inmunología , Células Cultivadas , Femenino , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Interferón-alfa/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Índice de Severidad de la Enfermedad
13.
J Clin Invest ; 131(14)2021 07 15.
Artículo en Inglés | MEDLINE | ID: covidwho-1311204

RESUMEN

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.


Asunto(s)
Autoanticuerpos/inmunología , COVID-19/complicaciones , COVID-19/inmunología , Interferón Tipo I/antagonistas & inhibidores , Interferón Tipo I/inmunología , Poliendocrinopatías Autoinmunes/complicaciones , Poliendocrinopatías Autoinmunes/inmunología , SARS-CoV-2 , Adolescente , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/sangre , Femenino , Humanos , Técnicas In Vitro , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/inmunología , Masculino , Poliendocrinopatías Autoinmunes/genética , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Factores de Transcripción/genética , Replicación Viral/inmunología , Adulto Joven
14.
Curr Rheumatol Rep ; 23(8): 58, 2021 07 03.
Artículo en Inglés | MEDLINE | ID: covidwho-1293440

RESUMEN

PURPOSE OF REVIEW: In this article, I have reviewed current reports that explore differences and similarities between multisystem inflammatory syndrome in children (MIS-C) and other known multisystem inflammatory diseases seen in children, particularly Kawasaki disease. RECENT FINDINGS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus causing the COVID-19 disease which emerged in China in December 2019 and spread rapidly to the entire country and quickly to other countries. Currently, there is a pandemic of SARS-CoV-2 infection that results in 20% of patients admitted to hospital with illness, with 3% developing intractable acute respiratory distress syndrome (ARDS) with high mortality. However, pediatric COVID-19 is still reported to be a mild disease, affecting only 8% of children. Pathogenesis in children is comparable to adults. There are suggested impaired activation of IFN-alpha and IFN regulator 3, decreased cell response causing impaired viral defense, yet the clinical course is mild, and almost all children recover from the infection without major complications. Interestingly, there is a subset of patients that develop a late but marked immunogenic response to COVID-19 and develop MIS-C. Clinical features of MIS-C resemble certain pediatric rheumatologic diseases, such as Kawasaki disease (mucocutaneous lymph node syndrome) which affects small-medium vessels. Other features of MIS-C resemble those of macrophage activation syndrome (MAS). However, recent research suggests distinct clinical and laboratory differences between MIS-C, Kawasaki disease, and MAS. Since the start of the SARS-CoV-2 pandemic, MIS-C has become the candidate for the most common cause of acquired heart disease in children.


Asunto(s)
COVID-19/inmunología , Síndrome de Activación Macrofágica/inmunología , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , COVID-19/fisiopatología , Humanos , Inmunidad Celular/inmunología , Factor 3 Regulador del Interferón/inmunología , Interferón-alfa/inmunología , Síndrome de Activación Macrofágica/fisiopatología , Síndrome Mucocutáneo Linfonodular/fisiopatología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología
15.
Immunopharmacol Immunotoxicol ; 43(3): 259-264, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: covidwho-1238100

RESUMEN

Coronavirus disease 2019 (COVID-19) is associated with irreversible effects on vital organs, especially the respiratory and cardiac systems. While the immune system plays a key role in the survival of patients to viral infections, in COVID-19, there is a hyperinflammatory immune response evoked by all the immune cells, such as neutrophils, monocytes, and includes release of various cytokines, resulting in an exaggerated immune response, named cytokine storm. This severe, dysregulated immune response causes multi-organ damage, which eventually leads to high mortality. One of the most important components of hypersensitivity is immunoglobulin E (IgE), which plays a major role in susceptibility to respiratory infections and can lead to the activation of mast cells. There is also a negative association between IgE and IFN-α, which can reduce Toll-like receptor (TLR) nine receptor expression and TLR-7 signaling to disrupt IFN production. Moreover, anti-IgE drugs such as omalizumab reduces the severity and duration of COVID-19. In addition to its anti-IgE effect, omalizumab inhibits inflammatory cells such as neutrophils. Hence, blockade of IgE may have clinical utility as an immunotherapy for COVID-19.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Omalizumab/uso terapéutico , Transducción de Señal/efectos de los fármacos , Humanos , Inmunoglobulina E/inmunología , Interferón-alfa/inmunología , Omalizumab/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 7/inmunología
16.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: covidwho-1066211

RESUMEN

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes , COVID-19 , Enfermedades Genéticas Congénitas , Interferón-alfa , Receptor de Interferón alfa y beta , SARS-CoV-2 , Vacuna contra la Fiebre Amarilla , Virus de la Fiebre Amarilla , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , COVID-19/genética , COVID-19/inmunología , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/inmunología , Células HEK293 , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/inmunología , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacuna contra la Fiebre Amarilla/efectos adversos , Vacuna contra la Fiebre Amarilla/genética , Vacuna contra la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/genética , Virus de la Fiebre Amarilla/inmunología
17.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artículo en Inglés | MEDLINE | ID: covidwho-1060966

RESUMEN

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Asunto(s)
COVID-19/inmunología , Interferón-alfa/inmunología , Interleucina-18/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Lavado Broncoalveolar , Estudios de Casos y Controles , Chlorocebus aethiops , Estudios de Cohortes , Femenino , Francia , Humanos , Inmunofenotipificación , Interleucina-10/inmunología , Interleucina-15/inmunología , Interleucina-1beta/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , RNA-Seq , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis de la Célula Individual , Células Vero , Adulto Joven
18.
Eur Rev Med Pharmacol Sci ; 24(23): 12536-12544, 2020 12.
Artículo en Inglés | MEDLINE | ID: covidwho-995014

RESUMEN

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.


Asunto(s)
COVID-19/inmunología , Citocinas/inmunología , Subgrupos de Linfocitos T/inmunología , Anciano , Anciano de 80 o más Años , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/sangre , COVID-19/mortalidad , COVID-19/terapia , Femenino , Humanos , Interferón-alfa/inmunología , Interleucina-10/inmunología , Interleucina-12/inmunología , Interleucina-17/inmunología , Interleucina-1beta/inmunología , Interleucina-2/inmunología , Interleucina-4/inmunología , Interleucina-5/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Antígenos Comunes de Leucocito/inmunología , Estudios Longitudinales , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pronóstico , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/inmunología
19.
JAMA Dermatol ; 157(2): 202-206, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: covidwho-959045

RESUMEN

Importance: Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown. Objective: To perform a systematic clinical, histologic, and biologic assessment in a cohort of patients with chilblain-like lesions occurring during the COVID-19 pandemic. Design, Setting, and Participants: In this prospective case series carried out with a COVID-19 multidisciplinary consultation group at the University Hospital of Nice, France, 40 consecutive patients presenting with chilblain-like lesions were included. Main Outcomes and Measures: Patients underwent a thorough general and dermatologic examination, including skin biopsies, vascular investigations, biologic analyses, interferon-alpha (IFN-α) stimulation and detection, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) and serologic analysis. Results: Overall, 40 consecutive patients with chilblain-like lesions were included. Most patients were young, with a median (range) age of 22 (12-67) years; 19 were male and 21 were female. The clinical presentation was highly reproducible with chilblain-like lesions mostly on the toes. Bullous and necrotic evolution was observed in 11 patients. Acrocyanosis or cold toes were reported in 19 (47.5%) cases. Criteria compatible with COVID-19 cases were noted in 11 (27.5%) within 6 weeks prior to the eruption. The real-time PCR (rt-PCR) testing results were negative in all cases. Overall, SARS-CoV-2 serology results were positive in 12 patients (30%). D-dimer concentration levels were elevated in 24 (60.0%) cases. Cryoglobulinemia and parvovirus B19 serologic results were negative for all tested patients. The major histologic findings were features of lymphocytic inflammation and vascular damage with thickening of venule walls and pericyte hyperplasia. A significant increase of IFN-α production after in vitro stimulation was observed in the chilblain population compared with patients with mild-severe acute COVID-19. Conclusions and Relevance: Taken together, our results suggest that chilblain-like lesions observed during the COVID-19 pandemic represent manifestations of a viral-induced type I interferonopathy. Trial Registration: ClinicalTrials.gov Identifier: NCT04344119.


Asunto(s)
COVID-19/complicaciones , Eritema Pernio/etiología , Adolescente , Adulto , Anciano , COVID-19/inmunología , Eritema Pernio/inmunología , Niño , Femenino , Humanos , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
20.
J Virol ; 94(23)2020 11 09.
Artículo en Inglés | MEDLINE | ID: covidwho-772280

RESUMEN

SARS-CoV-2, a novel coronavirus (CoV) that causes COVID-19, has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While distinct from SARS-CoV, both group 2B CoVs share similar genome organization, origins to bat CoVs, and an arsenal of immune antagonists. In this report, we evaluate type I interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication to SARS-CoV, the novel CoV is much more sensitive to IFN-I. In Vero E6 and in Calu3 cells, SARS-CoV-2 is substantially attenuated in the context of IFN-I pretreatment, whereas SARS-CoV is not. In line with these findings, SARS-CoV-2 fails to counteract phosphorylation of STAT1 and expression of ISG proteins, while SARS-CoV is able to suppress both. Comparing SARS-CoV-2 and influenza A virus in human airway epithelial cultures, we observe the absence of IFN-I stimulation by SARS-CoV-2 alone but detect the failure to counteract STAT1 phosphorylation upon IFN-I pretreatment, resulting in near ablation of SARS-CoV-2 infection. Next, we evaluated IFN-I treatment postinfection and found that SARS-CoV-2 was sensitive even after establishing infection. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonists. The absence of an equivalent open reading frame 3b (ORF3b) and genetic differences versus ORF6 suggest that the two key IFN-I antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to IFN-I responses between SARS-CoV and SARS-CoV-2 that may help inform disease progression, treatment options, and animal model development.IMPORTANCE With the ongoing outbreak of COVID-19, differences between SARS-CoV-2 and the original SARS-CoV could be leveraged to inform disease progression and eventual treatment options. In addition, these findings could have key implications for animal model development as well as further research into how SARS-CoV-2 modulates the type I IFN response early during infection.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Interferón Tipo I/farmacología , Interferón-alfa/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Animales , Antivirales/antagonistas & inhibidores , Antivirales/metabolismo , Betacoronavirus/inmunología , Betacoronavirus/fisiología , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Interferón Tipo I/antagonistas & inhibidores , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/inmunología , Interferón-alfa/metabolismo , Fosforilación , Proteínas Recombinantes/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2 , Factor de Transcripción STAT1/metabolismo , Transducción de Señal , Células Vero , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA