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1.
Viruses ; 13(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34452468

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), a global pandemic characterized by an exaggerated immune response and respiratory illness. Age (>60 years) is a significant risk factor for developing severe COVID-19. To better understand the host response of the aged airway epithelium to SARS-CoV-2 infection, we performed an in vitro study using primary human bronchial epithelial cells from donors >67 years of age differentiated on an air-liquid interface culture. We demonstrate that SARS-CoV-2 infection leads to early induction of a proinflammatory response and a delayed interferon response. In addition, we observed changes in the genes and pathways associated with cell death and senescence throughout infection. In summary, our study provides new and important insights into the temporal kinetics of the airway epithelial innate immune response to SARS-CoV-2 in older individuals.


Assuntos
Brônquios/imunologia , Brônquios/virologia , Imunidade Inata , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , SARS-CoV-2/imunologia , Idoso , Envelhecimento/imunologia , Brônquios/citologia , Brônquios/metabolismo , COVID-19/imunologia , Morte Celular/genética , Células Cultivadas , Senescência Celular/genética , Citocinas/biossíntese , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Humanos , Inflamação , Interferons/biossíntese , Interferons/genética , Masculino , RNA-Seq , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , SARS-CoV-2/fisiologia , Transdução de Sinais/genética
2.
Emerg Microbes Infect ; 10(1): 1626-1637, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34365904

RESUMO

Coronaviruses (CoVs) can infect a variety of hosts, including humans, livestock and companion animals, and pose a serious threat to human health and the economy. The current COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed millions of people. Unfortunately, effective treatments for CoVs infection are still lacking, suggesting the importance of coronavirus vaccines. Our previous work showed that CoV nonstuctural protein 14 (nsp14) functions as (guanine-N7)-methyltransferase (N7-MTase), which is involved in RNA cap formation. Moreover, we found that N7-MTase is well conserved among different CoVs and is a universal target for developing antivirals against CoVs. Here, we show that N7-MTase of CoVs can be an ideal target for designing live attenuated vaccines. Using murine hepatitis virus strain A59 (MHV-A59), a representative and well-studied model of coronaviruses, we constructed N7-MTase-deficient recombinant MHV D330A and Y414A. These two mutants are highly attenuated in mice and exhibit similar replication efficiency to the wild-type (WT) virus in the cell culture. Furthermore, a single dose immunization of D330A or Y414A can induce long-term humoral immune responses and robust CD4+ and CD8+ T cell responses, which can provide full protection against the challenge of a lethal-dose of MHV-A59. Collectively, this study provides an ideal strategy to design live attenuated vaccines for coronavirus by abolishing viral RNA N7-MTase activity. This approach may apply to other RNA viruses that encode their own conservative viral N7-methyltransferase.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Atenuadas/imunologia , Animais , Vacinas contra COVID-19/administração & dosagem , Citocinas/biossíntese , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Interferon Tipo I/biossíntese , Masculino , Camundongos , Mutação , Vacinas Atenuadas/administração & dosagem , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia
3.
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
4.
J Clin Invest ; 131(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34263736

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.


Assuntos
COVID-19/etiologia , Pneumonia Viral/etiologia , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/fisiologia , Autopsia , COVID-19/epidemiologia , COVID-19/patologia , Citocinas/biossíntese , Humanos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Modelos Biológicos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Receptores Virais/fisiologia , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
6.
Clin Immunol ; 229: 108798, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34280578

RESUMO

Inflammatory response in patients with COPD secondary to organic dust exposure (OD-COPD) is poorly understood. We therefore aimed to characterize inflammatory and immune profile from peripheral blood mononuclear cells (PBMC) in a group of patients with mild-to-moderate COPD secondary to organic dust exposure (OD-COPD), tobacco smoking (T-COPD), or both. We compared T, B and NK cells distribution and inflammatory (TNF-α, Il-1ß, IL-6), type 1 (IFN-γ), type 2 (IL-4, IL-13) and type 3 (IL-17) immunity related cytokines at baseline, and after stimulation with LPS, flagellin and CD3/CD28 beads in all COPD groups. OD-COPD displayed significantly lower NK cells and CD8+ T cells compared with controls. After flagellin stimulation, T-COPD had significantly lower IL-13 levels than OD-COPD and controls (p < 0.05) whereas IFN-γ tended to be lower in OD-COPD. All COPD groups displayed higher IL-1ß and IL-17 than controls after CD3/CD28 stimulation. Inflammatory responses in OD-COPD were different from T-COPD. OD-COPD displayed higher levels of type 2 immunity related cytokines.


Assuntos
Poeira/imunologia , Compostos Orgânicos/toxicidade , Doença Pulmonar Obstrutiva Crônica/imunologia , Idoso , Agricultura , Linfócitos B/imunologia , Linfócitos B/patologia , Estudos de Casos e Controles , Citocinas/biossíntese , Feminino , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Fumar Tabaco/efeitos adversos
7.
Front Immunol ; 12: 595150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262555

RESUMO

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Rim/imunologia , Fígado/imunologia , Pulmão/imunologia , Miocárdio/imunologia , Pandemias , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Humanos , Imunidade/genética , Monócitos/imunologia , Neutrófilos/imunologia , Transcriptoma , Regulação para Cima/genética
8.
Aging (Albany NY) ; 13(13): 17227-17236, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34198264

RESUMO

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1ß, IL-6 and TNF-α transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Citocinas/biossíntese , Citocinas/genética , Fibroblastos/metabolismo , MicroRNAs/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/biossíntese , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Fator de Necrose Tumoral alfa
9.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204294

RESUMO

Persistent infection with High Risk-Human Papilloma Viruses (HR-HPVs) is a primary cause of cervical cancer worldwide. Vaginal-dysbiosis-associated bacteria were correlated with the persistence of HR-HPVs infection and with increased cancer risk. We obtained strains of the most represented bacterial species in vaginal microbiota and evaluated their effects on the survival of cervical epithelial cells and immune homeostasis. The contribution of each species to supporting the antiviral response was also studied. Epithelial cell viability was affected by culture supernatants of most vaginal-dysbiosis bacteria, whereas Lactobacillus gasseri or Lactobacillus jensenii resulted in the best stimulus to induce interferon-γ (IFN-γ) production by human mononuclear cells from peripheral blood (PBMCs). Although vaginal-dysbiosis-associated bacteria induced the IFN-γ production, they were also optimal stimuli to interleukin-17 (IL-17) production. A positive correlation between IL-17 and IFN-γ secretion was observed in cultures of PBMCs with all vaginal-dysbiosis-associated bacteria suggesting that the adaptive immune response induced by these strains is not dominated by TH1 differentiation with reduced availability of IFN-γ, cytokine most effective in supporting virus clearance. Based on these results, we suggest that a vaginal microbiota dominated by lactobacilli, especially by L. gasseri or L. jensenii, may be able to assist immune cells with clearing HPV infection, bypasses the viral escape and restores immune homeostasis.


Assuntos
Antibiose , Disbiose , Homeostase , Lactobacillus/fisiologia , Membrana Mucosa/imunologia , Membrana Mucosa/microbiologia , Vagina/imunologia , Vagina/microbiologia , Sobrevivência Celular , Citocinas/biossíntese , Células Epiteliais/metabolismo , Ácidos Graxos Voláteis/biossíntese , Feminino , Humanos , Vagina/metabolismo
10.
Signal Transduct Target Ther ; 6(1): 266, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253708

RESUMO

Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1ß and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.


Assuntos
COVID-19 , Células Endoteliais da Veia Umbilical Humana , Fatores de Transcrição Kruppel-Like/biossíntese , SARS-CoV-2 , COVID-19/genética , COVID-19/metabolismo , COVID-19/patologia , COVID-19/prevenção & controle , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/virologia , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Fatores de Transcrição Kruppel-Like/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética
11.
J Med Chem ; 64(13): 9365-9380, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34161728

RESUMO

Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.


Assuntos
Antígenos CD36/metabolismo , Compostos Macrocíclicos/farmacologia , Peptídeos Cíclicos/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
12.
Mol Cells ; 44(6): 401-407, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34120892

RESUMO

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is an ongoing pandemic disease. SARS-CoV-2-specific CD4+ and CD8+ T-cell responses have been detected and characterized not only in COVID-19 patients and convalescents, but also unexposed individuals. Here, we review the phenotypes and functions of SARS-CoV-2-specific T cells in COVID-19 patients and the relationships between SARS-CoV-2-specific T-cell responses and COVID-19 severity. In addition, we describe the phenotypes and functions of SARS-CoV-2-specific memory T cells after recovery from COVID-19 and discuss the presence of SARS-CoV-2-reactive T cells in unexposed individuals and SARS-CoV-2-specific T-cell responses elicited by COVID-19 vaccines. A better understanding of T-cell responses is important for effective control of the current COVID-19 pandemic.


Assuntos
Anticorpos Neutralizantes/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Imunidade Celular , SARS-CoV-2/patogenicidade , Anticorpos Antivirais/biossíntese , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/virologia , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Convalescença , Citocinas/biossíntese , Citotoxicidade Imunológica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Humoral , Memória Imunológica , Imunofenotipagem , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
13.
Mol Cells ; 44(6): 408-421, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34059561

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus-host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , COVID-19/terapia , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Replicação Viral/efeitos dos fármacos , COVID-19/imunologia , COVID-19/patologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Dexametasona/uso terapêutico , Combinação de Medicamentos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunização Passiva/métodos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Peptídeos/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Replicação Viral/imunologia
14.
Inflamm Res ; 70(7): 749-752, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34173853

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), and IL-6 which are key elements of cytokine storm are by nuclear factor κß (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches.


Assuntos
COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Fluorcarbonetos/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Animais , Citocinas/biossíntese , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , NF-kappa B/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia
15.
Clin Exp Immunol ; 205(3): 363-378, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34061349

RESUMO

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly throughout the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralizing antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of nine immunodominant epitopes and characterize T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR-αß sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , COVID-19/imunologia , COVID-19/terapia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/virologia , Células Clonais/imunologia , Células Clonais/virologia , Proteínas do Nucleocapsídeo de Coronavírus/química , Proteínas do Nucleocapsídeo de Coronavírus/genética , Citocinas/biossíntese , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Imunização Passiva , Epitopos Imunodominantes/química , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
16.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072443

RESUMO

As an important zoonotic pathogen, Streptococcus suis (S. suis) infection has been reported to be a causative agent for variety of diseases in humans and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which is commonly seen in cases of severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of death. This calls for development of new strategies to avert the damage caused by STSLS. In this study, we found for the first time that Baicalein, combined with ampicillin, effectively improved severe S. suis infection. Further experiments demonstrated that baicalein significantly inhibited the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. Cell-based assays revealed that Baicalein did not exert toxic effects and conferred protection in S. suis-infected cells. Interestingly, compared with ampicillin alone, Baicalein combined with ampicillin resulted in a higher survival rate in mice severely infected with S. suis. At the same time, we found that baicalein can be combined with meropenem against MRSA. In conclusion, these results indicate that baicalein has a good application prospect.


Assuntos
Antibacterianos/farmacologia , Flavanonas/farmacologia , Infecções Estreptocócicas/microbiologia , Streptococcus suis/efeitos dos fármacos , Animais , Antibacterianos/química , Citocinas/biossíntese , Modelos Animais de Doenças , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada , Flavanonas/química , Hemólise/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/patologia , Relação Estrutura-Atividade
17.
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
18.
Nat Commun ; 12(1): 2783, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986294

RESUMO

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.


Assuntos
Proteínas CLOCK/genética , Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Cardiopatias/patologia , Monócitos/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Células Cultivadas , Ritmo Circadiano/genética , Citocinas/biossíntese , Fibrose/patologia , Hipertensão/genética , Hipertensão/patologia , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Receptores Acoplados a Proteínas G/metabolismo
19.
Toxicology ; 457: 152820, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34023435

RESUMO

Prolonged exposure to therapeutic hyperoxia can induce severe side effects on intestinal epithelial cells. Meanwhile, interleukin (IL)-17D secreted by intestinal epithelial cells, plays an important role in the mucosal immune system. Therefore, this study aimed to investigate the changes of IL-17D, IL-4 and IL-6 and the regulatory effect of nuclear factor erythroid 2-related factor 2 (Nrf2) on IL-17D, IL-4 and IL-6 under hyperoxia in human intestinal epithelial cells. To achieve this, NCM460 cells were exposed to an atmosphere containing 85 % oxygen (hyperoxia) for 24 h, 48 h, or 72 h; tert-butylhydroquinone (tBHQ) and ML385 were used as an Nrf2 activator and inhibitor, respectively. Immunohistochemical staining, western blot, and reverse transcription-quantitative polymerase chain reaction were performed to detect the expression levels of IL-17D, Nrf2, Kelch-like ECH-associated protein 1 (Keap1), IL-6, and IL-4 in NCM460 cells. Results showed that hyperoxia significantly increased the expression of IL-17D, Nrf2, IL-6, and IL-4, while decreasing that of Keap1. tBHQ further activated Nrf2 and promoted the expression of IL-17D, IL-6, and IL-4. Additionally, tBHQ aggravated hyperoxia-induced inflammation caused by hyperoxia. In contrast, ML385 completely inhibited the expression of Nrf2 and IL-17D, transiently inhibited IL-6 and IL-4 expression, and did not influence Keap1 expression. These results cumulatively demonstrate that hyperoxia aggravates the inflammatory response in intestinal epithelial cells by activating the Nrf2/IL-17D axis.


Assuntos
Citocinas/biossíntese , Hiperóxia/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-17/biossíntese , Mucosa Intestinal/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Linhagem Celular , Citocinas/genética , Expressão Gênica , Humanos , Hiperóxia/patologia , Interleucina-17/genética , Mucosa Intestinal/patologia , Fator 2 Relacionado a NF-E2/genética
20.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 719-728, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33856026

RESUMO

Acute kidney injury (AKI) is a complex syndrome with an abrupt decrease of kidney function, which is associated with high morbidity and mortality. Sepsis is the common cause of AKI. Mounting evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of sepsis-induced AKI. In this study, we aimed to illustrate the function and mechanism of lncRNA SNHG14 in lipopolysaccharide (LPS)-induced AKI. We found that SNHG14 was highly expressed in the plasma of sepsis patients with AKI. SNHG14 inhibited cell proliferation and autophagy and promoted cell apoptosis and inflammatory cytokine production in LPS-stimulated HK-2 cells. Functionally, SNHG14 acted as a competing endogenous RNA (ceRNA) to negatively regulate miR-495-3p expression in HK-2 cells. Furthermore, we identified that HIPK1 is a direct target of miR-495-3p in HK-2 cells. We also revealed that the SNHG14/miR-495-3p/HIPK1 interaction network regulated HK-2 cell proliferation, apoptosis, autophagy, and inflammatory cytokine production upon LPS stimulation. In addition, we demonstrated that the SNHG14/miR-495-3p/HIPK1 interaction network regulated the production of inflammatory cytokines (TNF-α, IL-6, and IL-1ß) via modulating NF-κB/p65 signaling in LPS-challenged HK-2 cells. In conclusion, our findings suggested a novel therapeutic axis of SNHG14/miR-495-3p/HIPK1 to treat sepsis-induced AKI.


Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Células Epiteliais/metabolismo , Lipopolissacarídeos/efeitos adversos , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante/sangue , Sepse/sangue , Transdução de Sinais/genética , Apoptose/genética , Autofagia/genética , Estudos de Casos e Controles , Linhagem Celular Transformada , Proliferação de Células/genética , Citocinas/biossíntese , Células Epiteliais/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Túbulos Renais/citologia , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , Sepse/complicações , Transfecção
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