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1.
Biomed Res Int ; 2021: 9101082, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33542929

RESUMEN

Objective: To compare the difference of inflammatory cytokines and lymphocyte subsets between deceased patients and survivors with COVID-19. Methods: This retrospective study included 254 confirmed patients from 10 January to 11 March, 2020, at Tongji Hospital of Wuhan, China. Laboratory and immunologic features were collected and analyzed, and the main outcomes focused on inflammatory cytokines and lymphocyte subsets. Results: A trend of markedly higher levels of inflammatory cytokines as well as lower lymphocyte subset levels in deceased patients was observed compared with survivors. ROC curve analyses indicated that inflammatory cytokines and the decrease levels of T cell, Th (helper T cells) cell, Ts (suppressor T cells) cell, B cell, and NK cell along with Th/Ts ratio increase could be used to predict the death of COVID-19. Multivariate analyses showed that higher levels of IL-6, IL-8, and IL-10 remained significantly correlated with shorter survival time and that the amount of Ts cells was negatively associated with the possibility of death in COVID-19 patients. In conclusion, SARS-CoV-2 would cause lymphopenia and result in decreased lymphocyte subset cells, particularly in Ts cell counts, which further induces hyperinflammatory response and cytokine storm. IL-6, IL-8, IL-10, and Ts cell might be independent predictors for the poor outcome of COVID-19.


Asunto(s)
/inmunología , Citocinas/inmunología , Subgrupos Linfocitarios/inmunología , Anciano , Linfocitos B/inmunología , Biomarcadores/sangre , /epidemiología , China/epidemiología , Femenino , Humanos , Estimación de Kaplan-Meier , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , /aislamiento & purificación
2.
Front Immunol ; 12: 626235, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33584733

RESUMEN

Objectives: The coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19. Method: In this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19. Results: Our data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (P=0.004) and soluble IL-2Rα (P=0.025). Conclusion: The significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.


Asunto(s)
/sangre , Interleucina-8/sangre , Receptores de Interleucina-2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Citocinas/sangre , Citocinas/inmunología , Femenino , Humanos , Interleucina-8/inmunología , Recuento de Leucocitos , Recuento de Linfocitos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Receptores de Interleucina-2/inmunología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
3.
J R Soc Interface ; 18(175): 20200950, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33593209

RESUMEN

While the pathological mechanisms in COVID-19 illness are still poorly understood, it is increasingly clear that high levels of pro-inflammatory mediators play a major role in clinical deterioration in patients with severe disease. Current evidence points to a hyperinflammatory state as the driver of respiratory compromise in severe COVID-19 disease, with a clinical trajectory resembling acute respiratory distress syndrome, but how this 'runaway train' inflammatory response emerges and is maintained is not known. Here, we present the first mathematical model of lung hyperinflammation due to SARS-CoV-2 infection. This model is based on a network of purported mechanistic and physiological pathways linking together five distinct biochemical species involved in the inflammatory response. Simulations of our model give rise to distinct qualitative classes of COVID-19 patients: (i) individuals who naturally clear the virus, (ii) asymptomatic carriers and (iii-v) individuals who develop a case of mild, moderate, or severe illness. These findings, supported by a comprehensive sensitivity analysis, point to potential therapeutic interventions to prevent the emergence of hyperinflammation. Specifically, we suggest that early intervention with a locally acting anti-inflammatory agent (such as inhaled corticosteroids) may effectively blockade the pathological hyperinflammatory reaction as it emerges.


Asunto(s)
/inmunología , Células Epiteliales/inmunología , Células Epiteliales/virología , Inflamación/inmunología , Pulmón/fisiopatología , Corticoesteroides , Citocinas/inmunología , Epitelio/inmunología , Humanos , Pulmón/patología , Modelos Inmunológicos , /fisiopatología , /patogenicidad
4.
Nat Commun ; 12(1): 1087, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597530

RESUMEN

The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients.


Asunto(s)
Inmunoterapia/métodos , Melanoma/terapia , Monitorización Inmunológica/métodos , Espectrometría Raman/métodos , Quimiocina CX3CL1/inmunología , Quimiocina CX3CL1/metabolismo , Estudios de Cohortes , Citocinas/inmunología , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos/inmunología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , /inmunología , Ipilimumab/efectos adversos , Ipilimumab/inmunología , Ipilimumab/uso terapéutico , Melanoma/inmunología , Melanoma/metabolismo , Microscopía Confocal/métodos , Proyectos Piloto , Reproducibilidad de los Resultados
5.
Cytokine ; 140: 155439, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33524886

RESUMEN

BACKGROUND: Immunodeficiency has pivotal role in the pathogenesis of coronavirus disease 2019 (COVID-19). Several studies have indicated defects in the immune system of COVID-19 patients at different disease stages. Therefore, this study investigated whether alters in immune responses of COVID-19 patients may be considered as predicting factors for disease outcome. METHODS: The percentages of innate and adoptive immune cells in the recovered and dead patients with COVID-19, and healthy subjects were determined by flow cytometry. The levels of pro- and anti-inflammatory cytokines and other immune factors were also measured by enzyme-linked immunosorbent assay. RESULTS: At the first day of hospitalization, the frequencies of CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells in patients who died during treatment were significantly increased compared to recovered and healthy individuals (P < 0.0001). The recovered and dead patients had a significant increase in monocyte number in comparison with healthy subjects (P < 0.05). No significant change was observed in Th1 cell numbers between the recovered and dead patients while Th2, Th17 cell, and Treg percentages in death cases were significantly lower than healthy control and those recovered, unlike exhausted CD4 + and CD8 + T cells and activated CD4 + T cells (P < 0.0001-0.05). The activated CD8 + T cell was significantly higher in the recovered patients than healthy individuals (P < 0.0001-0.05). IL-1α, IL-1ß, IL-6, and TNF-α levels in patients were significantly increased (P < 0.0001-0.01). However, there were no differences in TNF-α and IL-1ß levels between dead and recovered patients. Unlike TGF-ß1 level, IL-10 was significantly increased in recovered patients (P < 0.05). Lymphocyte numbers in recovered patients were significantly increased compared to dead patients, unlike ESR value (P < 0.001-0.01). CRP value in recovered patients significantly differed from dead patients (P < 0.001). CONCLUSION: Changes in frequencies of some immune cells and levels of some immune factors may be considered as predictors of mortality in COVID-19 patients.


Asunto(s)
/inmunología , Citocinas/inmunología , Sistema Inmunológico/inmunología , Inmunidad/inmunología , Sobrevivientes/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , /virología , Citocinas/sangre , Femenino , Humanos , Sistema Inmunológico/citología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/clasificación , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología
6.
Emerg Microbes Infect ; 10(1): 266-276, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33522893

RESUMEN

SARS-CoV-2 has claimed 2,137,908 lives in more than a year. Some COVID-19 patients experience sudden and rapid deterioration with the onset of fatal cytokine storm syndrome (CSS), which have increased interest in CSS's mechanisms, diagnosis and therapy. Although the prototypic concept of CSS was first proposed 116 years ago, we have only begun to study and understand CSS for less than 30 years. Actually, diseases under CSS umbrella include familial/primary and secondary hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), infection-associated hemophagocytic syndrome, cytokine release syndrome (CRS), and cytokine storm (CS). Hematologic malignancies and autoimmune diseases that cause CSS are named malignancy-associated hemophagocytic syndrome (MAHS) and MAS, respectively. In-depth research on the pathogenesis of HLH/CSS has greatly increased the number of patients that were able to be definitively diagnosed with HLH/CSS. However, it should be emphasized that HLH/CSS diagnosis is difficult at the early stages due to the non-specific clinical signs and symptoms, which tends to result in missed and incorrect diagnoses. Therefore, clinicians should not only possess extensive clinical experience to ensure high sensitivity to the characteristics of HLH/CSS but must also be familiar with HLH-2004/2009 diagnostic criteria, and HScore methods. The paper concisely comment evolution of CSS classifications, cytokines associated with CSS, evolution of CSS diagnostic criteria and importance of the correct identification of hemophagocytes in diagnosing CSS, which is timely and may benefit clinicians familiar HLH-2004/2009 diagnostic criteria, and HScore methods. In addition, clinicians must also understand that there are some limitations to these diagnostic criteria. Abbreviations: aBMT: autologous bone marrow transplantation; CAR-T: chimeric antigen receptor-engineered T-cell; COVID-19: coronavirus disease 2019; CSS: cytokine storm syndrome; HLH: hemophagocytic lymphohistiocytosis; MAS: macrophage activation syndrome; CRS: cytokine release syndrome; CS: cytokine storm; MAHS: malignancy-associated hemophagocytic syndrome; IAHS: infection-associated hemophagocytic syndrome; fHLH/pHLH: familial/primary hemophagocytic lymphohistiocytosis; sHLH: secondary hemophagocytic lymphohistiocytosis; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TCR-T, T-cell receptor-engineered T-cell.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/inmunología , Animales , /genética , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/virología , Citocinas/genética , Citocinas/inmunología , Humanos , /fisiología
7.
Arch Virol ; 166(2): 545-557, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33409549

RESUMEN

The use of gamma-irradiated influenza A virus (γ-Flu), retains most of the viral structural antigens, represent a promising option for vaccine development. However, despite the high effectiveness of γ-Flu vaccines, the need to incorporate an adjuvant to improve vaccine-mediated protection seems inevitable. Here, we examined the protective efficacy of an intranasal gamma-irradiated HIN1 vaccine co-administered with a plasmid encoding mouse interleukin-28B (mIL-28B) as a novel adjuvant in BALB/c mice. Animals were immunized intranasally three times at one-week intervals with γ-Flu, alone or in combination with the mIL-28B adjuvant, followed by viral challenge with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific antibody, cellular and mucosal responses, and the balance of cytokines in the spleen IFN-γ, IL-12, and IL-4) and in lung homogenates (IL-6 and IL-10) were measured by ELISA. The lymphoproliferative activity of restimulated spleen cells was also determined by MTT assay. Furthermore, virus production in the lungs of infected mice was estimated using the Madin-Darby canine kidney (MDCK)/hemagglutination assay (HA). Our data showed that intranasal immunization with adjuvanted γ-Flu vaccine efficiently promoted humoral, cellular, and mucosal immune responses and efficiently decreased lung virus titers, all of which are associated with protection against challenge. This combination also reduced IL-6 and IL-10 levels in lung homogenates. The results suggest that IL-28B can enhance the ability of the vaccine to elicit virus-specific immune responses and could potentially be used as an effective adjuvant.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Citocinas/inmunología , Inmunidad Celular/inmunología , Inmunidad Mucosa/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/inmunología , Administración Intranasal/métodos , Animales , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Perros , Femenino , Inmunización/métodos , Vacunas contra la Influenza/inmunología , Pulmón/inmunología , Pulmón/virología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/virología , Vacunación/métodos
8.
Sci Rep ; 11(1): 1462, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33446817

RESUMEN

Cannabis sativa is widely used for medical purposes and has anti-inflammatory activity. This study intended to examine the anti-inflammatory activity of cannabis on immune response markers associated with coronavirus disease 2019 (COVID-19) inflammation. An extract fraction from C. sativa Arbel strain (FCBD) substantially reduced (dose dependently) interleukin (IL)-6 and -8 levels in an alveolar epithelial (A549) cell line. FCBD contained cannabidiol (CBD), cannabigerol (CBG) and tetrahydrocannabivarin (THCV), and multiple terpenes. Treatments with FCBD and a FCBD formulation using phytocannabinoid standards (FCBD:std) reduced IL-6, IL-8, C-C Motif Chemokine Ligands (CCLs) 2 and 7, and angiotensin I converting enzyme 2 (ACE2) expression in the A549 cell line. Treatment with FCBD induced macrophage (differentiated KG1 cell line) polarization and phagocytosis in vitro, and increased CD36 and type II receptor for the Fc region of IgG (FcγRII) expression. FCBD treatment also substantially increased IL-6 and IL-8 expression in macrophages. FCBD:std, while maintaining anti-inflammatory activity in alveolar epithelial cells, led to reduced phagocytosis and pro-inflammatory IL secretion in macrophages in comparison to FCBD. The phytocannabinoid formulation may show superior activity versus the cannabis-derived fraction for reduction of lung inflammation, yet there is a need of caution proposing cannabis as treatment for COVID-19.


Asunto(s)
Antiinflamatorios/farmacología , Cannabinoides/farmacología , Cannabis/química , Células Epiteliales/inmunología , Macrófagos/inmunología , Extractos Vegetales/farmacología , /inmunología , Células A549 , Antiinflamatorios/química , /patología , Cannabinoides/química , Citocinas/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Macrófagos/patología , Macrófagos/virología , Extractos Vegetales/química , Receptores de IgG/inmunología
9.
Int J Med Sci ; 18(3): 846-851, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33437221

RESUMEN

In the last 50 years we have experienced two big pandemics, the HIV pandemic and the pandemic caused by SARS-CoV-2. Both pandemics are caused by RNA viruses and have reached us from animals. These two viruses are different in the transmission mode and in the symptoms they generate. However, they have important similarities: the fear in the population, increase in proinflammatory cytokines that generate intestinal microbiota modifications or NETosis production by polymorphonuclear neutrophils, among others. They have been implicated in the clinical, prognostic and therapeutic attitudes.


Asunto(s)
/epidemiología , Infecciones por VIH/epidemiología , VIH-1/patogenicidad , Pandemias/historia , /patogenicidad , /inmunología , /transmisión , Citocinas/sangre , Citocinas/inmunología , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Miedo , Carga Global de Enfermedades/estadística & datos numéricos , Infecciones por VIH/inmunología , Infecciones por VIH/psicología , Infecciones por VIH/transmisión , VIH-1/inmunología , VIH-1/aislamiento & purificación , Historia del Siglo XX , Historia del Siglo XXI , Interacciones Huésped-Patógeno/inmunología , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Mortalidad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Pandemias/estadística & datos numéricos , Pronóstico , /aislamiento & purificación
10.
Life Sci ; 267: 118973, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33400932

RESUMEN

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.


Asunto(s)
Eosinófilos/inmunología , Trastornos Respiratorios/inmunología , Enfermedades Respiratorias/inmunología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Humanos , Pulmón/metabolismo , Pulmón/patología , Trastornos Respiratorios/metabolismo , Trastornos Respiratorios/fisiopatología , Enfermedades Respiratorias/metabolismo , Enfermedades Respiratorias/fisiopatología , Células Th2/inmunología , Células Th2/metabolismo
11.
Viruses ; 13(2)2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33499363

RESUMEN

Felid herpesvirus-1 (FeHV-1) is an important respiratory and ocular pathogen of cats and current vaccines are limited in duration and efficacy because they do not prevent infection, viral nasal shedding and latency. To address these shortcomings, we have constructed FeHV-1 gE-TK- and FeHV-1 PK- deletion mutants (gE-TK- and PK-) using bacterial artificial chromosome (BAC) mutagenesis and shown safety and immunogenicity in vitro. Here, we compare the safety and efficacy of a prime boost FeHV-1 gE-TK- and FeHV-1 PK- vaccination regimen with commercial vaccination in cats. Cats in the vaccination groups were vaccinated at 3-week intervals and all cats were challenge infected 3 weeks after the last vaccination. Evaluations included clinical signs, nasal shedding, virus neutralizing antibodies (VN), cytokine mRNA gene expression, post-mortem histology and detection of latency establishment. Vaccination with gE-TK- and PK- mutants was safe and resulted in significantly reduced clinical disease scores, pathological changes, viral nasal shedding, and viral DNA in the trigeminal ganglia (the site of latency) following infection. Both mutants induced VN antibodies and interferons after immunization. In addition, after challenge infection, we observed a reduction of IL-1ß expression, and modulation of TNFα, TGFß and IL10 expression. In conclusion, this study shows the merits of using FeHV-1 deletion mutants for prevention of FeHV-1 infection in cats.


Asunto(s)
Enfermedades de los Gatos/prevención & control , Infecciones por Herpesviridae/veterinaria , Inmunidad Innata , Varicellovirus/genética , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Enfermedades de los Gatos/virología , Gatos , Línea Celular , Citocinas/genética , Citocinas/inmunología , Eliminación de Gen , Infecciones por Herpesviridae/prevención & control , Inmunización Secundaria/veterinaria , Masculino , Varicellovirus/fisiología , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales/genética , Virulencia/genética , Replicación Viral , Esparcimiento de Virus
12.
Emerg Microbes Infect ; 10(1): 167-177, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33399033

RESUMEN

During routine molecular surveillance of SARS-CoV-2 performed at the National Reference Center of Respiratory Viruses (Lyon, France) (n = 229 sequences collected February-April 2020), two frameshifting deletions were detected in the open reading frame 6, at the same position (27267). While a 26-nucleotide deletion variant (D26) was only found in one nasopharyngeal sample in March 2020, the 34-nucleotide deletion (D34) was found within a single geriatric hospital unit in 5/9 patients and one health care worker in April 2020. Phylogeny analysis strongly suggested a nosocomial transmission of D34, with potential fecal transmission, as also identified in a stool sample. No difference in disease severity was observed between patients hospitalized in the geriatric unit infected with WT or D34. In vitro D26 and D34 characterization revealed comparable replication kinetics with the wild-type (WT), but differential host immune responses. While interferon-stimulated genes were similarly upregulated after infection with WT and ORF6 variants, the latter specifically induced overexpression of 9 genes coding for inflammatory cytokines in the NF-kB pathway, including CCL2/MCP1, PTX3, and TNFα, for which high plasma levels have been associated with severe COVID-19. Our findings emphasize the need to monitor the occurrence of ORF6 deletions and assess their impact on the host immune response.


Asunto(s)
/epidemiología , Infección Hospitalaria/virología , Variación Genética , Genoma Viral , Proteínas Virales/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , /virología , Infección Hospitalaria/epidemiología , Infección Hospitalaria/inmunología , Citocinas/inmunología , Femenino , Mutación del Sistema de Lectura , Francia/epidemiología , Hospitalización , Humanos , Inmunidad , Inflamación , Masculino , Filogenia , Eliminación de Secuencia , Proteínas Virales/inmunología
13.
Eur Rev Med Pharmacol Sci ; 25(1): 556-566, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33506949

RESUMEN

A novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a current outbreak of infection termed Coronavirus Disease 2019 (COVID-19) by the World Health Organization (WHO). COVID-19 is currently a global pandemic that may cause close to half a billion deaths around the world. Until now, there is no effective treatment for COVID-19. Quinacrine (Qx) has been used since the 1930s as preventive antimalarial compound. It is a recognized small molecule inhibitor of RNA virus replication, with known anti-prion activity, and identified as a potent Ebola virus inhibitor both in vitro and in vivo. Recently, Qx has showed anti-SARS-CoV-2 activity. Herein, we review the potential mechanisms associated with quinacrine as an antiviral compound.


Asunto(s)
Antivirales/farmacología , Quinacrina/farmacología , Animales , Antivirales/administración & dosificación , Antivirales/efectos adversos , Línea Celular , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Citocinas/inmunología , Humanos , Ratones , Quinacrina/administración & dosificación , Quinacrina/efectos adversos , Replicación Viral/efectos de los fármacos
14.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33479167

RESUMEN

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.


Asunto(s)
/inmunología , Sistema Mononuclear Fagocítico/inmunología , /inmunología , Adulto , /metabolismo , Citocinas/inmunología , Células Dendríticas/inmunología , Femenino , Humanos , Interferones/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Sistema Mononuclear Fagocítico/metabolismo , Índice de Severidad de la Enfermedad , Suecia
15.
J Sci Food Agric ; 101(3): 863-870, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33433910

RESUMEN

BACKGROUND: Protecting the intestinal mucosa from being destroyed helps reduce the inflammation caused by acute pancreatitis (AP). In this study, whether okra pectin (OP) could attenuate the inflammation of AP through protecting the intestinal barrier was investigated. RESULTS: OP was obtained from crude okra pectin (COP) through the purification by DEAE cellulose 52 column. Supplementation with OP or COP in advance reduced the severity of AP, as revealed by lower serum amylase and lipase levels, abated pancreatic edema, attenuated myeloperoxidase activity and pancreas histology. OP or COP inhibited the production of pancreatic proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6. In addition, the upregulation of AP-related proteins including ZO-1, occludin, the antibacterial peptide-defensin-1 (DEFB1) and cathelicidin-related antimicrobial peptide (CRAMP), as well as the histological examination of colon injuries, demonstrated that OP or COP provision could effectively maintain intestinal barrier function. Ultimately, dietary OP or COP supplementation could inhibit AP-induced intestinal inflammation. For the above, the effect of OP was better than COP. CONCLUSION: Dietary OP supplementation could be considered as a preventive method that effectively interferes with intestinal damage and attenuates inflammatory responses trigged by AP. © 2020 Society of Chemical Industry.


Asunto(s)
Abelmoschus/química , Ceruletida/efectos adversos , Mucosa Intestinal/efectos de los fármacos , Pancreatitis/tratamiento farmacológico , Pectinas/administración & dosificación , Extractos Vegetales/administración & dosificación , Animales , Citocinas/genética , Citocinas/inmunología , Frutas/química , Humanos , Mucosa Intestinal/inmunología , Masculino , Ratones , Ocludina/genética , Ocludina/inmunología , Pancreatitis/inducido químicamente , Pancreatitis/genética , Pancreatitis/inmunología , Pectinas/química , Extractos Vegetales/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/inmunología
16.
Biomolecules ; 11(1)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445810

RESUMEN

The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are pathophysiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections.


Asunto(s)
/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/inmunología , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Humanos
17.
Theranostics ; 11(1): 316-329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391477

RESUMEN

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Asunto(s)
Antiinflamatorios/uso terapéutico , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Inmunosupresores/uso terapéutico , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , /inmunología , Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Humanos , Inmunosupresores/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
18.
Nat Commun ; 12(1): 409, 2021 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-33462245

RESUMEN

Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.


Asunto(s)
Decitabina/farmacología , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/terapia , Linfocitos T/trasplante , Animales , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Citocinas/genética , Citocinas/inmunología , Metilación de ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Ratones , Neoplasias/sangre , Neoplasias/inmunología , Neoplasias/patología , RNA-Seq , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33402434

RESUMEN

Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines, and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of comorbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age; comorbidities such as obesity, diabetes, and hypertension; and dysregulated immune response. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8+ T cells and sufficient control of the innate immune response. Furthermore, the best treatment-or combination of treatments-depends on the preinfection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.


Asunto(s)
/tratamiento farmacológico , /inmunología , Simulación por Computador , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Humanos , Inmunidad Innata , Modelos Teóricos , Fenotipo , /genética , /fisiología
20.
J Diabetes Res ; 2021: 9526701, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33490288

RESUMEN

The induction of inflammation and cytokine storm was proposed to play a critical role in COVID-19. This study is aimed at investigating the relationship between glucose metabolism and the inflammatory state of inpatients with COVID-19. 71 inpatients with COVID-19 were classified into nondiabetes mellitus (NDM) group, impaired fasting glucose (IFG) group, and diabetes mellitus (DM) group. The average hospitalization days were significantly shorter in DM patients when compared with patients in the IFG group and NDM group. CD4+ T cell percentage was higher while CD8+ T cells percentage was lower in the DM group than those in the NDM group. The serum levels of IL-6, IL-2, IL-10, and INF-γ in the DM group were upregulated when compared with those in the NDM group. The serum levels of TNF-α, IL-4, IL-2, IL-10, and INF-γ were significantly higher in the DM group than those in the IFG group. A significant difference was observed in CD4+ T cell, CD4+/CD8+ ratio percentage, IL-6, and IL-10 between the NDM group and DM group with adjusted BMI. In conclusion, COVID-19 patients with elevated glucose levels have promoted cytokine profiles and immune response.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Diabetes Mellitus Tipo 2/inmunología , Mediadores de Inflamación/inmunología , /inmunología , Adulto , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , /epidemiología , Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Interacciones Huésped-Patógeno , Humanos , Mediadores de Inflamación/sangre , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Tiempo
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