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1.
Gene ; 764: 145083, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32860902

RESUMO

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Moringa oleifera/química , Extratos Vegetais/administração & dosagem , Insuficiência Renal/prevenção & controle , Triazinas/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Moléculas de Adesão Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Poluentes Ambientais/toxicidade , Etanol/química , Contaminação de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Insuficiência Renal/sangue , Insuficiência Renal/induzido quimicamente , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Triazinas/administração & dosagem
2.
Clin Dermatol ; 38(6): 607-612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33341195

RESUMO

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, immunologically mediated cutaneous adverse reaction characterized by mucous membrane and epidermal detachment, with a mortality ranging from 15% to 25%. Risk factors for the development of SJS/TEN include immune dysregulation, active malignancy, and genetic predisposition. Medications are the most common cause, particularly antimicrobials, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory medications. Drug-specific CD8 T-cells and natural killer cells are thought to be the major inducers of keratinocyte apoptosis via release of soluble cytotoxic mediators, including Fas ligand, perforin/granzyme, tumor necrosis factor, and granulysin. When SJS/TEN is suspected clinically, appropriate therapy should be instituted without delay. All patients should be managed initially in an intensive care unit or burn unit under a multidisciplinary team of physicians experienced in the care of patients with SJS/TEN. Available data support the use of various pharmacologic agents to halt disease progression and improve outcomes, but no single drug has been found to be superior or beneficial for all patients. Future research should focus on developing a better understanding of the genetic susceptibility and immunopathophysiology of the disease, as well as novel diagnostic and therapeutic targets to improve patient outcomes.


Assuntos
Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/imunologia , Anti-Infecciosos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteína Ligante Fas/metabolismo , Predisposição Genética para Doença , Humanos , Doenças do Sistema Imunitário/complicações , Queratinócitos/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/complicações , Perforina/metabolismo , Fatores de Risco , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/terapia , Fator de Necrose Tumoral alfa/metabolismo
4.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037188

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Assuntos
Apoptose/imunologia , Betacoronavirus/patogenicidade , Caspase 8/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Necroptose/imunologia , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Animais , Caspase 8/genética , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Proc Natl Acad Sci U S A ; 117(40): 24957-24963, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32963096

RESUMO

B lymphocytes acquire self-reactivity as an unavoidable byproduct of antibody gene diversification in the bone marrow and in germinal centers (GCs). Autoreactive B cells emerging from the bone marrow are silenced in a series of well-defined checkpoints, but less is known about how self-reactivity that develops by somatic mutation in GCs is controlled. Here, we report the existence of an apoptosis-dependent tolerance checkpoint in post-GC B cells. Whereas defective GC B cell apoptosis has no measurable effect on autoantibody development, disruption of post-GC apoptosis results in accumulation of autoreactive memory B cells and plasma cells, antinuclear antibody production, and autoimmunity. The data presented shed light on mechanisms that regulate immune tolerance and the development of autoantibodies.


Assuntos
Apoptose/genética , Autoimunidade/genética , Genes de Imunoglobulinas/genética , Tolerância Imunológica/genética , Animais , Anticorpos Antinucleares/imunologia , Apoptose/imunologia , Autoanticorpos/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Genes de Imunoglobulinas/imunologia , Centro Germinativo/imunologia , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Camundongos , Plasmócitos/imunologia
7.
PLoS One ; 15(9): e0239176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936839

RESUMO

Polymyositis and inclusion body myositis are idiopathic inflammatory myopathies, with a pathology characterized by partial invasion of non-necrotic muscle fibres by CD8+ cytotoxic T-cells, leading to fibre degeneration. Although the main effector pathway of CD8+ T-cells is to induce apoptosis of target cells, it has remained unclear if apoptosis occurs in these diseases, and if so, if it is mediated by CD8+ T-cells. In consecutive biopsy sections from 10 patients with partial invasion, muscle fibres and inflammatory cells were assessed by immunohistochemistry and apoptotic nuclei by the TUNEL assay. Analysis of muscle fibre morphology, staining pattern and quantification were performed on digital images, and they were compared with biopsies from 10 dermatomyositis patients and 10 controls without muscle disease. Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8+ T-cells, granzyme B+ cells and macrophages, but lacked FAS receptor expression. In contrast, apoptotic myonuclei were rare in dermatomyositis and absent in controls. The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8+ cytotoxic T- cells, acting in parallel to the process of partial invasion.


Assuntos
Apoptose/imunologia , Fibras Musculares Esqueléticas/patologia , Miosite de Corpos de Inclusão/imunologia , Polimiosite/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Biópsia , Estudos de Coortes , Feminino , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/imunologia , Miosite de Corpos de Inclusão/patologia , Polimiosite/patologia
8.
Mol Immunol ; 126: 111-119, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32818819

RESUMO

Here, we aimed to investigate the role of long noncoding RNA (lncRNA) THRIL in septic-induced acute lung injury. C57BL/6 mice were injected with Adenoviruses (Ad)-shTHRIL or negative control (NC) before caecal ligation and puncture (CLP) operation. MPVECs were transfected with Ad-shTHRIL or NC, followed by lipopolysaccharide (LPS) treatment. MiR-424 and Rho-associated kinase 2 (ROCK2) were predicted and verified as direct targets of THRIL and miR-424, respectively, by using dual-luciferase reporter assay. ROCK2 overexpression vector and shTHRIL were co-transfected into mouse pulmonary microvascular endothelial cells for 24 h before LPS treatment. Our results showed that THRIL was highly expressed in the lung of sepsis mice. CLP triggered severe lung injury and apoptosis in mice, which was abolished by THRIL knockdown. Moreover, CLP treatment visibly increased protein concentration, the number of total cell of neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). Besides, elevated protein levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were observed in both lung and BALF. However, inhibition of THRIL reduced the number of inflammatory cells and the production of pro-inflammatory cytokines in sepsis mouse model. The effect of THRIL on inflammatory response and apoptosis in the lung was confirmed in sepsis cell model. Moreover, mechanistic studies have shown that THRIL up-regulated ROCK2 level through sponging miR-424. Furthermore, ROCK2 overexpression reversed the inhibitory effects of THRIL knockdown on LPS-induced inflammatory response and apoptosis. Overall, in vivo and in vitro results suggested that THRIL accelerates sepsis-induced lung injury by sponging miR-424 and further restoring ROCK2.


Assuntos
Lesão Pulmonar Aguda/imunologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Sepse/complicações , Quinases Associadas a rho/genética , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/genética , Apoptose/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais , Endotélio Vascular/citologia , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/imunologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Microvasos/citologia , Sepse/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia
9.
Ecotoxicol Environ Saf ; 203: 111006, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32684520

RESUMO

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-κB (NF-κB) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology.


Assuntos
Poluentes Ambientais/toxicidade , Sistema Imunitário/efeitos dos fármacos , Níquel/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Citocinas/metabolismo , Humanos , Sistema Imunitário/crescimento & desenvolvimento , Sistema Imunitário/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
10.
Eur J Cancer ; 135: 62-65, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32544799

RESUMO

While confirmed cases of the deadly coronavirus disease 2019 (COVID-19) have exceeded 4.7 million globally, scientists are pushing forward with efforts to develop vaccines and treatments in an attempt to slow the pandemic and lessen the disease's damage. Although no proven effective therapies for treating patients with COVID-19 or for managing their complications currently exist, the rapidly expanding knowledge regarding severe acute respiratory syndrome coronavirus 2 and its interplay with hosts provides a significant number of potential drug targets and the potential to repurpose drugs already tested in other diseases. Herein, we report the biological rationale of immune-activating drugs and a brief summary of literature data on the potential therapeutic value of immune checkpoint inhibitors that have been recently tested beyond cancer treatment for their potential to restore cellular immunocompetence.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Imunológicos/farmacologia , Linfopenia/sangue , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , Neoplasias/sangue , Neoplasias/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
11.
Nat Commun ; 11(1): 2177, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358581

RESUMO

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.


Assuntos
Astrocitoma/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Microglia/imunologia , Midkina/metabolismo , Neurofibromatose 1/metabolismo , Neurônios/metabolismo , Glioma do Nervo Óptico/imunologia , Animais , Apoptose/imunologia , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Quimiocina CCL4/metabolismo , Quimiocina CCL5/metabolismo , Criança , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurofibromatose 1/genética , Glioma do Nervo Óptico/mortalidade , Glioma do Nervo Óptico/patologia , Microambiente Tumoral/imunologia
12.
Nat Med ; 26(6): 919-931, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451498

RESUMO

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Microbioma Gastrointestinal/imunologia , Íleo/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Oxaliplatina/farmacologia , Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/uso terapêutico , Apoptose/imunologia , Bacteroides fragilis , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Firmicutes , Microbioma Gastrointestinal/fisiologia , Humanos , Íleo/imunologia , Íleo/microbiologia , Íleo/patologia , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/imunologia , Vigilância Imunológica/efeitos dos fármacos , Vigilância Imunológica/imunologia , Interleucina-12/imunologia , Mucosa Intestinal , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
13.
Nature ; 582(7810): 104-108, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32427965

RESUMO

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.


Assuntos
Apoptose/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Parasitos/imunologia , Plasmodium falciparum/citologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Aotidae/imunologia , Aotidae/parasitologia , Caspases/metabolismo , Criança , Estudos de Coortes , DNA de Protozoário/química , DNA de Protozoário/metabolismo , Ativação Enzimática , Eritrócitos/parasitologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Quênia , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Masculino , Camundongos , Parasitos/citologia , Parasitos/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/química , Tanzânia , Trofozoítos/citologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/imunologia , Vacúolos/imunologia
14.
Proc Natl Acad Sci U S A ; 117(23): 12961-12968, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32444487

RESUMO

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Evasão da Resposta Imune , Linfócitos T Citotóxicos/imunologia , Animais , Apoptose/imunologia , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular , Técnicas de Cocultura , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/virologia , Modelos Animais de Doenças , Fibroblastos , Granzimas/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Camundongos , Camundongos Knockout , Muromegalovirus/genética , Muromegalovirus/imunologia , Muromegalovirus/metabolismo , Mutagênese , Perforina/genética , Perforina/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Imagem com Lapso de Tempo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
15.
Nat Commun ; 11(1): 2362, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398673

RESUMO

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy.


Assuntos
Alarminas/imunologia , Células Estreladas do Fígado/imunologia , Hepatócitos/metabolismo , Cirrose Hepática/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alarminas/metabolismo , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hepatócitos/citologia , Hepatócitos/imunologia , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Fagocitose/imunologia , Tioacetamida/toxicidade , Adulto Jovem
16.
J Gen Virol ; 101(6): 645-650, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32391749

RESUMO

Lumpy skin disease virus (LSDV), a Capripoxvirus, is of economic importance in the cattle industry and is controlled by vaccination. A comparison was made of the host response to the two LSDV vaccines Neethling and Herbivac LS, with reference to the well-studied Orthopoxvirus, modified vaccinia Ankara (MVA), in a mouse model. Because the vaccines differ at the superoxide dismutase homologue (SOD) gene locus, recombinant SOD knock-out and knock-in nLSDV vaccines were constructed and all four vaccines were tested for the induction and inhibition of apoptosis. The SOD homologue was associated both with induction of apoptosis as well as inhibition of camptothecin-induced apoptosis. Histological analysis of chorioallantoic membranes of fertilized hens' eggs infected with the four different vaccines indicated marked mesodermal proliferation associated with vaccines containing the full-length SOD homologue as well as increased immune cell infiltration. Our findings suggest that the SOD homologue may influence vaccine immunogenicity.


Assuntos
Apoptose/genética , Interações Hospedeiro-Patógeno/genética , Doença Nodular Cutânea/genética , Doença Nodular Cutânea/virologia , Vírus da Doença Nodular Cutânea/genética , Superóxido Dismutase/genética , Transcrição Genética/genética , Animais , Apoptose/imunologia , Bovinos , Galinhas/imunologia , Galinhas/virologia , Feminino , Doença Nodular Cutânea/imunologia , Vírus da Doença Nodular Cutânea/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Superóxido Dismutase/imunologia , Transcrição Genética/imunologia , Vacinação/métodos , Vacinas Atenuadas/imunologia , Vírus Vaccinia/genética , Vírus Vaccinia/imunologia , Vacinas Virais/imunologia
17.
Sci Rep ; 10(1): 7173, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346066

RESUMO

To evaluate the effect of GuttaFlow bioseal (GFB) and MTA Fillapex (MTAF) in comparison with Endofill (EF) in the subcutaneous tissue. Polyethylene tubes with GFB, MTAF, EF or empty tubes (control group; CG) were implanted into subcutaneous of rats. After 7, 15, 30 and 60 days, the capsule thickness, inflammatory reaction, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), caspase-3, TUNEL-positive cells, von Kossa and ultrastructural features were evaluated. The data were statistically analyzed (p ≤ 0.05). At all periods, the number of IL-6- and VEGF-immunolabelled cells, and capsule thickness were lower in GFB than MTAF, which was lower than EF (p < 0.0001). At 60 days, the number of inflammatory cells was similar in GFB and MTAF (p = 0.58). Significant differences in the number of TUNEL- and caspase-3-positive cells were not observed among GFB, MTAF and CG whereas the highest values were found in EF specimens. The EF specimens exhibited several cells with condensed chromatin, typical of apoptosis. von Kossa-positive and birefringent structures were only observed in GFB and MTAF, suggesting the presence of calcite crystals. Taken together, these results show that cellular and structural damage induced by GFB and MTAF sealers were recovery over time. Moreover, these sealers express bioactive potential in subcutaneous tissue.


Assuntos
Apoptose/efeitos dos fármacos , Dimetilpolisiloxanos/farmacologia , Guta-Percha/farmacologia , Materiais Restauradores do Canal Radicular/farmacologia , Tela Subcutânea/imunologia , Animais , Apoptose/imunologia , Caspase 3/imunologia , Combinação de Medicamentos , Inflamação/imunologia , Inflamação/patologia , Interleucina-6/imunologia , Masculino , Ratos , Ratos Sprague-Dawley , Tela Subcutânea/patologia , Fator A de Crescimento do Endotélio Vascular/imunologia
18.
Mol Immunol ; 120: 113-121, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32113131

RESUMO

Litopenaeus vannamei, as an important marine aquaculture species, has attracted more and more attentions in past several years. More recently people got its genome fine mapping, which unveiled a gene treasure. In this study, we have identified a novel trypsin-like protein which came from previous WSSV-infected shrimp plasma iTRAQ data. This protein is a 39 kDa protein with 363 amino acids. It contains a conserved trypsin-domain and could be strongly induced with WSSV infection. Interestingly, knockdown of this protein made shrimps vulnerable to WSSV infection. Further exploration unveiled that this fragility was probably due to the fact that knockdown of this protein could cause shrimp hemocytes apoptosis, which indicated that this protein played key roles in preventing shrimp hemocytes from apoptosis. To further explore how LvTLAP protected shrimp hemocytes from apoptosis, GST pull down assay was applied to screen LvTLAP interacting protein in shrimp plasma. L. vannamei growth and transformation-dependent-like protein (LvGTD-like protein) was identified as a LvTLAP interacting protein, which played proapoptotic roles in cells. Thus, a possible explanation for LvTLAP anti-apoptosis activity was that this protein could block LvGTD-like protein proapoptotic activity to protect shrimp hemocytes from death. In general, our study has uncovered a novel WSSV responsive shrimp plasma protein, which played key roles in shrimp hemocytes anti-apoptosis and shrimp against WSSV infection.


Assuntos
Proteínas Sanguíneas/imunologia , Penaeidae/imunologia , Penaeidae/virologia , Vírus da Síndrome da Mancha Branca 1/patogenicidade , Sequência de Aminoácidos , Animais , Apoptose/genética , Apoptose/imunologia , Apoptose/fisiologia , Sequência de Bases , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , DNA/genética , Técnicas de Silenciamento de Genes , Hemócitos/metabolismo , Hemócitos/patologia , Hemócitos/virologia , Penaeidae/genética
19.
Sci Rep ; 10(1): 5109, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198370

RESUMO

Splenic immune function was enhanced in diet-induced-obese (DIO) mice caused by Escherichia coli. The changes in spleen function on apoptosis were still unknown. Two hundred mice in groups Lean-E. coli and DIO-E. coli were intranasal instillation of E. coli. And another two hundred mice in groups Lean-PBS and DIO-PBS were given phosphate-buffered saline (PBS). Subsequently, spleen histology was analyzed. Then the rates of spleen cell (SC) apoptosis, and expression of the genes and proteins of Bcl-2, Bax, caspase-3 and caspase-9 were quantified in each group at 0 h (uninfected), 12 h, 24 h, and 72 h postinfection. The SC apoptosis rates of the DIO-E. coli groups were lower than those of the DIO-PBS groups at 12, 24 and 72 h (p < 0.05). Anti-apoptotic Bcl-2 expression gene and protein of the DIO-E. coli groups were higher than those of the DIO-PBS groups (p < 0.05). Gene expressions of pro-apoptotic Bax, caspase-3 and caspase-9 of the DIO-E. coli groups were lower than those of DIO-PBS groups at 12, 24 and 72 h (p < 0.05). The SC apoptosis rates of the Lean-E. coli groups were higher than those of the Lean- PBS groups at 12 h and 24 h (p < 0.05). Interestingly, the SC apoptosis rates in the DIO-E. coli groups were lower than those of the Lean-E. coli groups at 12 h (p < 0.05). In conclusion, our results suggested that the DIO mice presented stronger anti-apoptotic abilities than Lean mice in non-fatal acute pneumonia induced by E. coli infection, which is more conducive to protecting the spleen and improving the immune defense ability of the body.


Assuntos
Apoptose/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/imunologia , Obesidade/imunologia , Pneumonia/imunologia , Baço/imunologia , Administração Intranasal , Animais , Caspase 3/biossíntese , Caspase 9/biossíntese , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/mortalidade , Macrófagos/imunologia , Masculino , Megacariócitos/imunologia , Camundongos , Camundongos Obesos , Neutrófilos/imunologia , Pneumonia/microbiologia , Pneumonia/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Baço/citologia , Proteína X Associada a bcl-2/biossíntese
20.
Mol Immunol ; 121: 99-110, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199212

RESUMO

The complement cascade consists of cell bound and serum proteins acting together to protect the host from pathogens, remove cancerous cells and effectively links innate and adaptive immune responses. Despite its usefulness in microbial neutralization and clearance of cancerous cells, excessive complement activation causes an immune imbalance and tissue damage in the host. Hence, a series of complement regulatory proteins present at a higher concentration in blood plasma and on cell surfaces tightly regulate the cascade. The complement cascade can be initiated by B-1 B cell production of natural antibodies. Natural antibodies arise spontaneously without any known exogenous antigenic or microbial stimulus and protect against invading pathogens, clear apoptotic cells, provide tissue homeostasis, and modulate adaptive immune functions. Natural IgM antibodies recognize microbial and cancer antigens and serve as an activator of complement mediated lysis. This review will discuss advances in complement activation and regulation in bacterial and viral infections, and cancer. We will also explore the crosstalk of natural antibodies with bacterial populations and cancer.


Assuntos
Infecções Bacterianas/imunologia , Imunidade Humoral , Imunidade Inata , Neoplasias/imunologia , Viroses/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo , Evasão Tumoral
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