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3.
PLoS One ; 15(7): e0214497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639963

RESUMO

The Bashbay sheep (Ovis aries), an indigenous breed of Xinjiang, China, has many excellent characteristics. It is resistant to Mycoplasma ovipneumoniae infection, the causative agent of mycoplasma ovipneumonia, a chronic respiratory disease that is harmful to the sheep industry. To date, knowledge regarding the mechanisms responsible for M. ovipneumoniae pathogenesis in scant. Herein, we report the results of transcriptome profiling of lung tissues from Bashbay sheep experimentally infected with an M. ovipneumoniae strain at 4 and 14 days post-infection, in comparison to mock-infected animals (0 d). Transcriptome profiling was performed by deep RNA sequencing, using the Illumina platform. The analysis of differentially expressed genes was performed to determine concomitant gene-specific temporal patterns of mRNA expression in the lungs after M. ovipneumoniae infection. We found 1048 differentially expressed genes (575 up-regulated, 473 down-regulated) when comparing transcriptomic data at 4 and 0 days post-infection, and 2823 (1362 up-regulated, 1461 down-regulated) when comparing 14 versus 0 days post-infection. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the differentially expressed genes at 4 and 14 versus 0 days post-infection were enriched in 245 and 287 pathways, respectively, and the Toll-like receptor (TLR) signaling pathway was considered most closely related to MO infection (p < 0.01). Two pathways (LAMP-TLR2/TLR6-MyD88-MKK6-AP1-IL1B and LAMP-TLR8MyD88-IRF5-RANTES) were identified based on the TLR signaling pathway from differentially expressed genes related M. ovipneumoniae infection. Gene Ontology analysis showed that differentially expressed genes in different groups were enriched for 1580 and 4561 terms, where those most closely related to M. ovipneumoniae infection are positive regulators of inflammatory responses (p < 0.01). These results could aid in understanding how M. ovipneumoniae infection progresses in the lungs and may provide useful information regarding key regulatory pathways.


Assuntos
Pulmão/metabolismo , Pneumonia por Mycoplasma/patologia , Análise de Sequência de RNA/métodos , Doenças dos Ovinos/patologia , Transcriptoma , Animais , Regulação para Baixo , Mycoplasma ovipneumoniae/isolamento & purificação , Mycoplasma ovipneumoniae/patogenicidade , Pneumonia por Mycoplasma/genética , Pneumonia por Mycoplasma/veterinária , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ovinos , Doenças dos Ovinos/genética , Doenças dos Ovinos/metabolismo , Transdução de Sinais/genética , Fatores de Tempo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Regulação para Cima
4.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604797

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
5.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: covidwho-623805

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
6.
Anticancer Res ; 40(8): 4445-4455, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727774

RESUMO

BACKGROUND/AIM: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs. RESULTS: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC. CONCLUSION: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.


Assuntos
Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Interferons/metabolismo , Neoplasias Pancreáticas/genética , Poli I-C/farmacologia , Receptores Toll-Like/genética , Idoso , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
7.
FASEB J ; 34(7): 8787-8795, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525600

RESUMO

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Ativação do Complemento/genética , Infecções por Coronavirus/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Receptores Virais/genética , Receptores Toll-Like/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/genética , Resistência à Doença/imunologia , Predisposição Genética para Doença , Variação Genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação , Metagenômica , Mutação de Sentido Incorreto , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Prognóstico , Locos de Características Quantitativas , Receptores Virais/fisiologia , Risco , Receptores Toll-Like/imunologia , Resultado do Tratamento
8.
Parasitol Res ; 119(8): 2505-2510, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32535733

RESUMO

Human trichinellosis is acquired by eating raw or undercooked meats carrying muscle larvae of Trichinella spp. Toll-like receptors (TLRs) are essential components of the innate immune system. However, little is known about the potential application of TLR agonists for immunotherapy against Trichinella spiralis (T. spiralis) infection. Here, we evaluated the effects of four TLR agonists (i.e., TLR3, TLR4, TLR8, and TLR9 agonists) on T. spiralis infection in mice. The reduction rate of worm burden showed that TLR3 agonist poly(I:C) significantly reduced T. spiralis infection rather than TLR4, TLR8, and TLR9 agonists (p < 0.05). Moreover, TLR3 showed a continuous high-level of expression during 6-35 days post infection (dpi). The levels of interferon-gamma (IFN-γ), interleukin (IL)-2, and IL-6 increased significantly in mice serum compared with control group after treatment with TLR3 agonist at 0, 3, 6, 9, 12, 15, 18, 21, 28, and 35 dpi (p < 0.05). A significant decreasing trend was also detected in levels of IL-10 and IL-4 after treatment with TLR3 agonist compared with control group at 0, 3, 6, 9, 12, 15, 18, 21, 28, and 35 dpi (p < 0.05). Overall, this study suggested that TLR3-targeted therapies might be effective on worm burden reduction by regulation of the cytokine levels in the mice infected with T. spiralis.


Assuntos
Receptores Toll-Like/imunologia , Trichinella spiralis/imunologia , Triquinelose/imunologia , Animais , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Larva/genética , Larva/imunologia , Larva/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores Toll-Like/genética , Trichinella spiralis/genética , Trichinella spiralis/fisiologia , Triquinelose/parasitologia
9.
FASEB J ; 34(7): 8787-8795, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-593467

RESUMO

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Ativação do Complemento/genética , Infecções por Coronavirus/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Receptores Virais/genética , Receptores Toll-Like/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/genética , Resistência à Doença/imunologia , Predisposição Genética para Doença , Variação Genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação , Metagenômica , Mutação de Sentido Incorreto , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Prognóstico , Locos de Características Quantitativas , Receptores Virais/fisiologia , Risco , Receptores Toll-Like/imunologia , Resultado do Tratamento
10.
Signal Transduct Target Ther ; 5(1): 84, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467561

RESUMO

To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Terapia de Alvo Molecular , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
11.
Clin Immunol ; 215: 108448, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353634

RESUMO

The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/genética , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Gerenciamento Clínico , Regulação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
12.
PLoS Pathog ; 16(5): e1008586, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453782

RESUMO

The murine innate immune response against Toxoplasma gondii is predominated by the interaction of TLR11/12 with Toxoplasma profilin. However, mice lacking Tlr11 or humans, who do not have functional TLR11 or TLR12, still elicit a strong innate immune response upon Toxoplasma infection. The parasite factors that determine this immune response are largely unknown. Herein, we investigated two dense granule proteins (GRAs) secreted by Toxoplasma, GRA15 and GRA24, for their role in stimulating the innate immune response in Tlr11-/- mice and in human cells, which naturally lack TLR11/TLR12. Our results show that GRA15 and GRA24 synergistically shape the early immune response and parasite virulence in Tlr11-/- mice, with GRA15 as the predominant effector. Nevertheless, acute virulence in Tlr11-/- mice is still dominated by allelic combinations of ROP18 and ROP5, which are effectors that determine evasion of the immunity-related GTPases. In human macrophages, GRA15 and GRA24 play a major role in the induction of IL12, IL18 and IL1ß secretion. We further show that GRA15/GRA24-mediated IL12, IL18 and IL1ß secretion activates IFNγ secretion by peripheral blood mononuclear cells (PBMCs), which controls Toxoplasma proliferation. Taken together, our study demonstrates the important role of GRA15 and GRA24 in activating the innate immune response in hosts lacking TLR11.


Assuntos
Imunidade Inata/imunologia , Macrófagos/imunologia , Proteínas de Protozoários/imunologia , Receptores Toll-Like/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Humanos , Imunidade Inata/genética , Macrófagos/parasitologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Células RAW 264.7 , Receptores Toll-Like/genética , Toxoplasmose/genética , Toxoplasmose/patologia
13.
Arterioscler Thromb Vasc Biol ; 40(7): 1635-1650, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434410

RESUMO

OBJECTIVE: Thrombocytopenia is associated with many viral infections suggesting virions interact with and affect platelets. Consistently, viral particles are seen inside platelets, and platelet activation markers are detected in viremic patients. In this article, we sought mechanistic insights into these virion/platelet interactions by examining how platelets endocytose, traffic, and are activated by a model virion. Approach and Results: Using fluorescently tagged HIV-1 pseudovirions, 3-dimensional structured illumination microscopy, and transgenic mouse models, we probed the interactions between platelets and virions. Mouse platelets used known endocytic machinery, that is, dynamin, VAMP (vesicle-associated membrane protein)-3, and Arf6 (ADP-ribosylation factor 6), to take up and traffic HIV-1 pseudovirions. Endocytosed HIV-1 pseudovirions trafficked through early (Rab4+) and late endosomes (Rab7+), and then to an LC3+ (microtubule-associated protein 1A/1B-light chain 3) compartment. Incubation with virions induced IRAK4 (interleukin 1 receptor-associated kinase 4), Akt (protein kinase B), and IKK (IκB kinase) activation, granule secretion, and platelet-leukocyte aggregate formation. This activation required TLRs (Toll-like receptors) and MyD88 (myeloid differentiation primary response protein 88) but was less extensive and slower than activation with thrombin. In vivo, HIV-1 pseudovirions injection led to virion uptake and platelet activation, as measured by IKK activation, platelet-leukocyte aggregate formation, and mild thrombocytopenia. All were decreased in VAMP-3-/- and, megakaryocyte/platelet-specific, Arf6-/- mice. Similar platelet activation profiles (increased platelet-leukocyte aggregates, plasma platelet factor 4, and phospho-IκBα) were detected in newly diagnosed and antiretroviral therapy-controlled HIV-1+ patients. CONCLUSIONS: Collectively, our data provide mechanistic insights into the cell biology of how platelets endocytose and process virions. We propose a mechanism by which platelets sample the circulation and respond to potential pathogens that they take up.


Assuntos
Plaquetas/metabolismo , Endocitose , Infecções por HIV/sangue , HIV-1/patogenicidade , Ativação Plaquetária , Trombocitopenia/sangue , Receptores Toll-Like/sangue , Vírion , Fatores de Ribosilação do ADP/sangue , Fatores de Ribosilação do ADP/genética , Animais , Antirretrovirais/uso terapêutico , Plaquetas/virologia , Agregação Celular , Células Cultivadas , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Quinase I-kappa B/sangue , Quinase I-kappa B/genética , Leucócitos/metabolismo , Leucócitos/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/sangue , Fator 88 de Diferenciação Mieloide/genética , Fator Plaquetário 4/sangue , Fator Plaquetário 4/genética , Trombocitopenia/diagnóstico , Trombocitopenia/virologia , Receptores Toll-Like/deficiência , Receptores Toll-Like/genética , Proteína 3 Associada à Membrana da Vesícula/sangue , Proteína 3 Associada à Membrana da Vesícula/genética
14.
Signal Transduct Target Ther ; 5(1): 84, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: covidwho-437295

RESUMO

To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Terapia de Alvo Molecular , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
15.
Clin Immunol ; 215: 108448, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-125370

RESUMO

The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/genética , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Gerenciamento Clínico , Regulação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/imunologia
16.
PLoS One ; 15(5): e0233714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469968

RESUMO

Toll-like receptor (TLR) genes have recently been employed to assess genetic diversity, as they can be used to infer both demographic history and adaptation to environments with different pathogen pressure. Here, we sampled 120 individuals of the Chinese egret (Egretta eulophotes), a globally vulnerable species, from four breeding populations across China. We assessed the levels of genetic diversity, selection pressure, and population differentiation at seven TLR loci (TLR1LB, TLR2A, TLR3, TLR4, TLR5, TLR7, and TLR15). Using a variety of metrics (SNPs, heterozygosity, nucleotides, haplotypes), our analyses showed that genetic diversity was lower at 4 of the 7 TLR loci in the vulnerable Chinese egret compared to the more common little egret (Egretta garzetta). The selection test indicated TLRs, except for TLR5, were under purifying selection in TLR evolution, suggesting that low TLR genetic diversity in the Chinese egret may be caused by purifying selection. Moreover, analysis of molecular variance indicated low but significant population differentiation among four populations at all of the TLR loci in this egret. However, some comparisons based on fixation index analyses did not show significant population differentiation, and Bayesian clustering showed admixture. Our finding suggested that these four populations of the Chinese egret in China may be considered a single unit for conservation planning. These results, the new report of TLR genetic diversity in a long-distance migratory vulnerable Ardeid species, will provide fundamental TLR information for further studies on the conservation genetics of the Chinese egret and other Ardeids.


Assuntos
Proteínas Aviárias/genética , Aves/genética , Variação Genética , Receptores Toll-Like/genética , Animais , China
17.
PLoS One ; 15(4): e0231399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32276269

RESUMO

Vibrio coralliilyticus is a pathogen of coral and mollusk, contributing to dramatic losses worldwide. In our study, we found that V. coralliilyticus challenge could directly affect adult Tridacna crocea survival; there were dead individuals appearing at 6 h post infection, and there were 45.56% and 56.78% mortality rates in challenged groups after 36 h of infection. The apoptosis rate of hemocytes was significantly increased by 1.8-fold at 6 h after V. coralliilyticus injection. To shed light on the mechanistic molecular responses of T. crocea to V. coralliilyticus infection, we used transcriptome sequencing analysis and other relevant techniques to analyze T. crocea hemocytes at 0 h, 6 h, 12 h and 24 h after V. coralliilyticus challenge. Our results revealed that the total numbers of unigenes and DEGs were 195651 and 3446, respectively. Additional details were found by KEGG pathway enrichment analysis, where DEGs were significantly enriched in immune-related signaling pathways, such as the TLR signaling pathway, and some were associated with signaling related to apoptosis. Quantitative validation results illustrated that with exposure to V. coralliilyticus, the expression of TLR pathway members, TLR, MyD88, IRAK4, TRAF6, and IкB-α, were significantly upregulated (by 22.9-, 9.6-, 4.0-, 3.6-, and 3.9-fold, respectively) at 6 h. The cytokine-related gene IL-17 exhibited an increase of 6.3-fold and 10.5-fold at 3 h and 6 h, respectively. The apoptosis-related gene IAP1 was dramatically increased by 2.99-fold at 6 h. These results indicate that adult T. crocea could initiate the TLR pathway to resist V. coralliilyticus, which promotes the release of inflammatory factors such as IL-17 and leads to the activation of a series of outcomes, such as apoptosis. The response mechanism is related to the T. crocea immunoreaction stimulated by V. coralliilyticus, providing a theoretical basis for understanding T. crocea immune response mechanisms.


Assuntos
Bivalves/imunologia , Transcriptoma , Vibrio/patogenicidade , Animais , Bivalves/genética , Bivalves/microbiologia , Citocinas/genética , Citocinas/metabolismo , Hemócitos/metabolismo , Hemócitos/microbiologia , Imunidade Inata , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
18.
PLoS Biol ; 18(3): e3000663, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203540

RESUMO

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as 'suicidal' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.


Assuntos
Espermatozoides/fisiologia , Receptores Toll-Like/metabolismo , Cromossomo X , Animais , Evolução Biológica , Humanos , Masculino , Transporte de RNA , Razão de Masculinidade , Espermatogênese , Espermatozoides/citologia , Espermatozoides/metabolismo , Receptores Toll-Like/genética
19.
Autoimmun Rev ; 19(4): 102496, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062033

RESUMO

In recent years, there has been a significant amount of interest and vigorous studies on mutations related to innate immunity receptor genes such as Toll-like receptors (TLR), which is driven by the identification of many associations between these mutations and development of various disorders leading, in particular, to autoimmune diseases. It has been proven that the occurrence of single nucleotide polymorphisms in DNA sequences encoding TLRs causes malfunction of some key signaling pathways, and, as a result, increases the risk of autoimmune diseases. The identification of these polymorphisms can lead to the understanding of the pathogenesis of autoimmune diseases, which subsequently will create effective methods for the prevention and treatment thereof. This article examines the current state of the art, in particular summarizes data on the role of polymorphisms in Toll-like receptor genes in a number of autoimmune endocrine diseases, including type 1 diabetes mellitus, Graves' disease and Hashimoto's autoimmune thyroiditis. The search for relevant scientific data was carried out by entering search queries based on keywords: TLR, SNP, autoimmunity, Graves' disease, Type 1 diabetes mellitus, Hashimoto's autoimmune thyroiditis. The search was conducted through PubMed, MEDLINE, Elsevier journals, Science Direct and Russian Index of Scientific Citation, as well as other highly cited publications on Genetics, Immunology, and Pathophysiology - related to the topic.


Assuntos
Doenças Autoimunes/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Toll-Like/genética , Diabetes Mellitus Tipo 1/genética , Doença de Graves/genética , Doença de Hashimoto/genética , Humanos , Tireoidite Autoimune/genética
20.
PLoS One ; 15(2): e0228958, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32069296

RESUMO

Obstructive sleep apnea (OSA) is a syndrome leading to chronic intermittent hypoxia, and the up-regulation of toll-like receptors (TLR) 2 and 6 on peripheral blood cells has been reported. We hypothesized that DNA methylation in TLR2 and TLR6 genes may play a role in the development of OSA and its excessive daytime sleepiness (EDS) phenotype. DNA methylation over 28 cytosine-phosphate-guanine (CpG) sites of the TLR2 promoter region and 3 CpG sites of the TLR6 gene body, and their protein expressions were measured by using pyrosequencing and ELISA methods in 18 heathy subjects (HS) and 58 patients with severe OSA (divided into 18 non-EDS and 40 EDS group). Patients with severe OSA had higher DNA methylation levels over five CpG sites (#1, #2, #3, #25 and #28) and lower DNA methylation levels over CpG site #18 of the TLR2 promoter region, higher DNA methylation levels over two CpG sites (#1 and #3) of the TLR6 gene body, and higher protein expressions of TLR6 than HS. The CpG site #2 of the TLR6 gene body was hypermethylated in severe OSA patients with EDS. Both DNA methylation levels over CpG site #1 of the TLR6 gene body and protein expressions of TLR6 were reduced after more than 6 months of nasal CPAP treatment in seven selected patients. Aberrant DNA methylation of the TLR2 promoter region and TLR6 gene body are associated with the consequence of severe OSA and its EDS phenotype.


Assuntos
Apneia Obstrutiva do Sono/genética , Receptor 2 Toll-Like/genética , Receptor 6 Toll-Like/genética , Adulto , Estudos de Casos e Controles , Pressão Positiva Contínua nas Vias Aéreas/métodos , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polissonografia/métodos , Regiões Promotoras Genéticas/genética , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/fisiopatologia , Taiwan , Receptor 2 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , Receptores Toll-Like/genética
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