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1.
BMC Infect Dis ; 21(1): 639, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215212

RESUMO

BACKGROUND: Infection by chikungunya (CHIKV) and dengue virus (DENV) can cause a wide spectrum of clinical features, many of which are undifferentiated. Cytokines, which broadly also include chemokines and growth factors, have been shown to play a role in protective immunity as well as DENV and CHIKV pathogenesis. However, differences in cytokine response to both viruses remain poorly understood, especially in patients from countries where both viruses are endemic. Our study is therefore aimed to provide a comparative profiling of cytokine response induced by acute DENV and CHIKV infections in patients with similar disease stages and in experimental in vitro infections. METHODS: By using multiplex immunoassay, we compared host cytokine profiles between acute CHIKV and DENV infections by analysing serum cytokine levels of IL-1α, IL-4, IL-5, IL-8, IL-13, RANTES, MCP-3, eotaxin, PDGF-AB/BB, and FGF-2 from the sera of acute chikungunya and dengue fever patients. We further investigated the cytokine profile responses using experimental in vitro CHIKV and DENV infections of peripheral blood mononuclear cells (PBMCs). RESULTS: We found that both CHIKV and DENV-infected patients had an upregulated level of IL-8 and IL-4, with the highest IL-4 level observed in DENV-2 infected patients. Higher IL-8 level was also correlated with lower platelet count in dengue patients. IL-13 and MCP-3 downregulation was observed only in chikungunya patients, while conversely PDGF-AB/BB and FGF-2 downregulation was unique in dengue patients. Age-associated differential expression of IL-13, MCP-3, and IL-5 was also observed, while distinct kinetics of IL-4, IL-8, and FGF-2 expression between CHIKV and DENV-infected patients were identified. Furthermore, the unique pattern of IL-8, IL-13 and MCP-3, but not IL-4 expression was also recapitulated using experimental in vitro infection in PBMCs. CONCLUSIONS: Taken together, our study identified common cytokine response profile characterized by upregulation of IL-8 and IL-4 between CHIKV and DENV infection. Downregulation of IL-13 and MCP-3 was identified as a unique cytokine response profile of acute CHIKV infection, while distinct downregulation of PDGF-AB/BB and FGF-2 characterized the response from acute DENV infection. Our study provides an important overview of the host cytokine responses between CHIKV and DENV infection, which is important to further understand the mechanism and pathology of these diseases.


Assuntos
Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Citocinas/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Adolescente , Adulto , Idoso , Febre de Chikungunya/epidemiologia , Febre de Chikungunya/metabolismo , Febre de Chikungunya/virologia , Criança , Pré-Escolar , Estudos Transversais , Citocinas/imunologia , Dengue/epidemiologia , Dengue/metabolismo , Dengue/virologia , Feminino , Humanos , Indonésia/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
2.
Front Immunol ; 12: 649359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220807

RESUMO

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-α, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.


Assuntos
COVID-19/patologia , Leptina/imunologia , Obesidade/patologia , SARS-CoV-2/imunologia , Adipócitos/metabolismo , Células Apresentadoras de Antígenos/imunologia , COVID-19/mortalidade , Citocinas/imunologia , Suscetibilidade a Doenças/patologia , Humanos , Leptina/sangue , Monócitos/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Células Th1/imunologia
3.
Front Immunol ; 12: 698672, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220861

RESUMO

The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.


Assuntos
Adjuvantes Imunológicos/farmacologia , COVID-19/dietoterapia , Fosfatos de Cálcio/farmacologia , Suplementos Nutricionais , Glicopeptídeos/farmacologia , Imunomodulação/imunologia , SARS-CoV-2/efeitos dos fármacos , Vacinas contra COVID-19/imunologia , Citocinas/imunologia , Humanos , SARS-CoV-2/imunologia , Vacinação
4.
Cell Commun Signal ; 19(1): 73, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238338

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand-receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. METHODS: A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand-receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1ß, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. RESULTS: Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand-receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. CONCLUSIONS: Our study showed that macrophages driving ligand-receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1ß, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. TRIAL REGISTRATION: This is a retrospective observational study without a trial registration number. Video Abstract.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Comunicação Celular , Macrófagos/imunologia , Análise de Célula Única , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19/epidemiologia , COVID-19/fisiopatologia , China/epidemiologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas , Estudos Retrospectivos , Análise de Sequência de RNA , Índice de Gravidade de Doença
5.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207960

RESUMO

Psoriasis is an immune-mediated systemic disease that may be treated with probiotics. In this study, probiotic strains that could or could not decrease interleukin (IL)-17 levels were applied to imiquimod (IMQ)-induced psoriasis-like mice via oral administration. Bifidobacteriumadolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillusparacasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines, whereas B. animalis CCFM1148, L. paracasei CCFM1147, and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines. All effective strains increased the contents of short-chain fatty acids, which were negatively correlated with the levels of inflammatory cytokines. By performing 16S rRNA gene sequencing, the diversity of gut microbiota in psoriasis-like mice was found to decrease, but all effective strains made some specific changes to the composition of gut microbiota compared to the ineffective strains. Furthermore, except for B. breve CCFM1078, all other effective strains decreased the abundance of the family Rikenellaceae, which was positively correlated with psoriasis-like pathological characteristics and was negatively correlated with propionate levels. These findings demonstrated effects of strain-specificity, and how probiotics ameliorated psoriasis and provide new possibilities for the treatment of psoriasis.


Assuntos
Microbioma Gastrointestinal , Probióticos/uso terapêutico , Psoríase/dietoterapia , Psoríase/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bifidobacterium/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Imiquimode , Interleucinas/análise , Interleucinas/metabolismo , Lactobacillaceae/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Células Th17/imunologia
6.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207900

RESUMO

Cytokines play a huge role in many biological processes. Their production, release and interactions are subject to a very complex mechanism. Cytokines are produced by all types of cells, they function very differently and they are characterized by synergism in action, antagonism, and aggregation activity, opposing action of one cytokine, overlapping activity, induction of another cytokine, inhibition of cytokine synthesis at the mRNA level as well as autoregulation-stimulation or inhibition of own production. The predominance of pro-inflammatory cytokines leads to a systemic inflammatory response, and anti-inflammatory-to an anti-inflammatory response. They regulate the organism's immune response and protect it against sudden disturbances in homeostasis. The synthesis and activity of cytokines are influenced by the central nervous system through the endocrine system (pituitary gland, adrenal glands).


Assuntos
Citocinas , Leite Humano , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Homeostase/imunologia , Humanos , Leite Humano/imunologia , Leite Humano/metabolismo , Hipófise/imunologia , Hipófise/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209109

RESUMO

Atherosclerosis is a well-known global health problem. Despite the high prevalence of the disease, numerous aspects of pathogenesis remain unclear. Subsequently, there are still no cure or adequate preventive measures available. Atherogenesis is now considered a complex interplay between lipid metabolism alterations, oxidative stress, and inflammation. Inflammation in atherogenesis involves cellular elements of both innate (such as macrophages and monocytes) and adaptive immunity (such as B-cells and T-cells), as well as various cytokines cascades. Because inflammation is, in general, a well-investigated therapeutic target, and strategies for controlling inflammation have been successfully used to combat a number of other diseases, inflammation seems to be the preferred target for the treatment of atherosclerosis as well. In this review, we summarized data on targeting the most studied inflammatory molecular targets, CRP, IL-1ß, IL-6, IFN-γ, and TNF-α. Studies in animal models have shown the efficacy of anti-inflammatory therapy, while clinical studies revealed the incompetence of existing data, which blocks the development of an effective atheroprotective drug. However, all data on cytokine targeting give evidence that anti-inflammatory therapy can be a part of a complex treatment.


Assuntos
Imunidade Adaptativa , Anti-Inflamatórios/uso terapêutico , Aterosclerose , Citocinas/imunologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Aterosclerose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia
8.
Signal Transduct Target Ther ; 6(1): 256, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234102

RESUMO

We collected blood from coronavirus disease 2019 (COVID-19) convalescent individuals and investigated SARS-CoV-2-specific humoral and cellular immunity in these discharged patients. Follow-up analysis in a cohort of 171 patients at 4-11 months after the onset revealed high levels of IgG antibodies. A total of 78.1% (164/210) of the specimens tested positive for neutralizing antibody (NAb). SARS-CoV-2 antigen peptide pools-stimulated-IL-2 and -IFN-γ response can distinguish COVID-19 convalescent individuals from healthy donors. Interestingly, NAb survival was significantly affected by the antigen peptide pools-stimulated-IL-2 response, -IL-8 response, and -IFN-γ response. The antigen peptide pools-activated CD8+ T cell counts were correlated with NAb. The antigen peptide pools-activated natural killer (NK) cell counts in convalescent individuals were correlated with NAb and disease severity. Our data suggested that the development of NAb is associated with the activation of T cells and NK cells. Our work provides a basis for further analysis of the protective immunity to SARS-CoV-2 and for understanding the pathogenesis of COVID-19. It also has implications for the development of an effective vaccine for SARS-CoV-2 infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Convalescença , Citocinas/imunologia , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Sci Immunol ; 6(61)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266981

RESUMO

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Saccharomycetales/genética , Glicoproteína da Espícula de Coronavírus/genética , Administração por Inalação , Administração Intranasal , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Citocinas/imunologia , Humanos , Imunoglobulina G/imunologia , Pulmão/patologia , Macaca mulatta , Masculino , Ligação Proteica , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
10.
Viruses ; 13(6)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207696

RESUMO

Mammalian cells have developed an elaborate network of immunoproteins that serve to identify and combat viral pathogens. Interferon-stimulated gene 15 (ISG15) is a 15.2 kDa tandem ubiquitin-like protein (UBL) that is used by specific E1-E2-E3 ubiquitin cascade enzymes to interfere with the activity of viral proteins. Recent biochemical studies have demonstrated how the E3 ligase HECT and RCC1-containing protein 5 (HERC5) regulates ISG15 signaling in response to hepatitis C (HCV), influenza-A (IAV), human immunodeficiency virus (HIV), SARS-CoV-2 and other viral infections. Taken together, the potent antiviral activity displayed by HERC5 and ISG15 make them promising drug targets for the development of novel antiviral therapeutics that can augment the host antiviral response. In this review, we examine the emerging role of ISG15 in antiviral immunity with a particular focus on how HERC5 orchestrates the specific and timely ISGylation of viral proteins in response to infection.


Assuntos
Citocinas/genética , Interferons/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ubiquitinas/genética , Viroses/imunologia , Animais , COVID-19/imunologia , Citocinas/imunologia , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Camundongos , SARS-CoV-2/imunologia , Ubiquitinas/imunologia , Proteínas Virais/genética , Proteínas Virais/metabolismo
11.
Crit Care ; 25(1): 236, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229735

RESUMO

Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood-brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation.


Assuntos
Encefalopatias/imunologia , COVID-19/complicações , Citocinas/imunologia , Influenza Humana/complicações , Malária/complicações , Sepse/complicações , Barreira Hematoencefálica/imunologia , Encefalopatias/prevenção & controle , COVID-19/imunologia , Humanos , Influenza Humana/imunologia , Malária/imunologia , Sepse/imunologia
12.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
13.
Front Immunol ; 12: 659419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079547

RESUMO

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) - 2.48 - 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.


Assuntos
Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Modelos Imunológicos , Viroses/complicações , Biomarcadores/sangue , Biomarcadores/metabolismo , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Carga Viral/imunologia , Viroses/sangue , Viroses/imunologia , Viroses/virologia
14.
Molecules ; 26(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070943

RESUMO

The medicinal plant noni (Morinda citrifolia) is widely dispersed throughout Southeast Asia, the Caribbean, and Australia. We previously reported that fermented Noni could alleviate atopic dermatitis (AD) by recovering Th1/Th2 immune balance and enhancing skin barrier function induced by 2,4-dinitrochlorobenzene. Noni has a high deacetylasperulosidic acid (DAA) content, whose concentration further increased in fermented noni as an iridoid constituent. This study aimed to determine the anti-AD effects and mechanisms of DAA on HaCaT, HMC-1, and EOL-1 cells. DAA inhibited the gene expression and secretion of AD-related cytokines and chemokines including interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-25, IL-33, thymic stromal lymphopoietin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, thymus and activation-regulated chemokine, macrophage-derived chemokine, and regulated upon activation, normal T cell expressed and secreted, in all cells, and inhibited histamine release in HMC-1 cells. DAA controlled mitogen-activated protein kinase phosphorylation levels and the translocation of nuclear factor-kappa light chain enhancer of activated B cells into the nucleus by inhibiting IκBα decomposition in all the cells. Furthermore, DAA increased the expression of proteins involved in skin barrier functions such as filaggrin and involucrin in HaCaT cells. These results confirmed that DAA could relieve AD by controlling immune balance and recovering skin barrier function.


Assuntos
Dermatite Atópica/tratamento farmacológico , Glicosídeos/farmacologia , Linhagem Celular , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Dermatite Atópica/patologia , Eczema/tratamento farmacológico , Eczema/patologia , Glicosídeos/metabolismo , Humanos , Queratinócitos/efeitos dos fármacos , Morinda/metabolismo , Extratos Vegetais/farmacologia , Pele/metabolismo , Equilíbrio Th1-Th2/efeitos dos fármacos
15.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071080

RESUMO

The main purpose of this study was to investigate whether the blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation have the potential to suppress the pathogenesis of allergic asthma by inhibition and/or enhancement of the production by CD4+ and CD8+ T cells of important cytokines promoting (i.e., IL-4 and IL-17) and/or inhibiting (i.e., IL-10 and TGF-ß), respectively, the development of allergic asthma. Studies using ovalbumin(OVA)-immunized mice have demonstrated that all the tested therapeutic strategies prevented the OVA-induced increase in the absolute number of IL-4- and IL-17-producing CD4+ T cells (i.e., Th2 and Th17 cells, respectively) indirectly, i.e., through the inhibition of the clonal expansion of these cells in the mediastinal lymph nodes. Additionally, the blockade of NF-κB translocation and RANKL/RANK interaction, but not IKK, prevented the OVA-induced increase in the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. These latter results strongly suggest that both therapeutic strategies can directly decrease IL-4 and IL-17 production by Th2 and Th17 cells, respectively. This action may constitute an important mechanism underlying the anti-asthmatic effect induced by the blockade of NF-κB translocation and of RANKL/RANK interaction. Thus, in this context, both these therapeutic strategies seem to have an advantage over the blockade of IKK. None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-ß-producing Treg cells, and hence they lacked the potential to inhibit the development of the disease via this mechanism.


Assuntos
Asma/imunologia , Asma/metabolismo , Animais , Asma/fisiopatologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade/fisiopatologia , Imunoglobulina E/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos
16.
Front Immunol ; 12: 658896, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149697

RESUMO

The COVID-19 pathomechanism depends on (i) the pathogenicity of the virus, (ii) ability of the immune system to respond to the cytopathic effect of the virus infection, (iii) co-morbidities. Inflammatory cytokine production constitutes a hallmark of COVID-19 that is facilitated by inability of adaptive immunity to control virus invasion. The effect of cytokine release syndrome is deleterious, but the severity of it depends on other confounding factors: age and comorbidities. In this study, we analyze the literature data on the post-transplant course of allogeneic hematopoietic stem cell transplanted (alloHSCT) patients, which is affected by generated inflammatory cytokines. The sequence of events boosting cytokine production was analyzed in relation to clinical and laboratory data highlighting the impact of cytokine generation on the post-transplant course. The collected data were compared to those from studies on COVID-19 patients. The similarities are: (i) the damage/pathogen-associated molecular pattern (DAMP/PAMP) stage is similar except for the initiation hit being sterile in alloHSCT (toxic damage of conditioning regimen) and viral in COVID-19; (ii) genetic host-derived factors play a role; (iii) adaptive immunity fails, DAMP signal(s) increases, over-production of cytokines occurs; (iv) monocytes lacking HLADR expression emerge, being suppressor cells hampering adaptive immunity; (v) immune system homeostasis is broken, the patient's status deteriorates to bed dependency, leading to hypo-oxygenation and malnutrition, which in turn stimulates the intracellular alert pathways with vigorous transcription of cytokine genes. All starts with the interaction between DAMPs with appropriate receptors, which leads to the production of pro-inflammatory cytokines, the inflammatory process spreads, tissue is damaged, DAMPs are released and a vicious cycle occurs. Attempts to modify intracellular signaling pathways in patients with post-alloHSCT graft vs host disease have already been undertaken. The similarities documented in this study show that this approach may also be used in COVID-19 patients for tuning signal transduction processes to interrupt the cycle that powers the cytokine overproduction.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunologia de Transplantes/imunologia , Aloenxertos , Citocinas/biossíntese , Citocinas/imunologia , Humanos , SARS-CoV-2
17.
Front Immunol ; 12: 601842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084159

RESUMO

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes.


Assuntos
Asma , Citocinas , Mediadores da Inflamação , Pulmão , Asma/imunologia , Asma/patologia , Asma/terapia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Pulmão/imunologia , Pulmão/patologia
18.
Genes Immun ; 22(3): 141-160, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140652

RESUMO

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.


Assuntos
Alarminas/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/imunologia , Viroses/imunologia , Alarminas/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Síndrome da Liberação de Citocina/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Imunológicos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/fisiologia , Viroses/complicações , Viroses/metabolismo
19.
Med Oncol ; 38(8): 90, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34191146

RESUMO

During the COVID-19 pandemic, it is important to assure the safety and management of cancer patients. Despite preliminary studies revealed that patients with cancer are more susceptible to infection and have poorer prognosis than other infected patients without cancer, mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. So, we have some comments about the pathogenesis attributed to the COVID-19 disease and cancer relationship and determination of subgroups in this and oncoming studies. Variable effects of anticancer treatments on the patient's immune system are yet to be elucidated. On the other hand, the effect of SARS-CoV-2 virus on tumor microenvironment or immune responses in cancer is not yet fully proven. Very recently, Challenor and her colleague reported a case with classical Hodgkin lymphoma with stage IIIs disease, which went into remission without corticosteroid or immunochemotherapy. They assumed that the putative mechanisms of action include cross-reactivity of pathogen-specific T cells with tumor antigens and natural killer cell activation by inflammatory cytokines produced in response to infection. During the course of COVID-19 disease, immune checkpoint blockade effect might be induced naturally.


Assuntos
COVID-19/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Reações Cruzadas , Citocinas/imunologia , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
20.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071276

RESUMO

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.


Assuntos
Anticorpos/farmacologia , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Imunização Passiva/métodos , Animais , Anticorpos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B , Autoanticorpos , LDL-Colesterol/sangue , Citocinas/imunologia , Humanos , Inflamação/tratamento farmacológico , Fragmentos de Peptídeos , Pró-Proteína Convertase 9/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico
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