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1.
Int J Biol Macromol ; 268(Pt 1): 131734, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38653431

RESUMO

SARS-CoV-2 infection results in cytokine burst, leading to proinflammatory responses in lungs of COVID-19 patients. SARS-CoV-2 ORF3a triggers the generation of proinflammatory cytokines. However, the underlying mechanism of dysregulation of proinflammatory responses is not well understood. We studied the role of microRNA in the generation of proinflammatory responses as a bystander effect of SARS-CoV-2 ORF3a in human lung epithelial cells. We observed upregulation of hsa-miR-155-5p in SARS-CoV-2 ORF3a transfected human lung epithelial cells, which led to the reduced expression of SHIP1. This resulted in phosphorylation of AKT and NF-κB, which further led to the increased expression of the proinflammatory cytokines IL-6 and TNF-α. Additionally, overexpression and knockdown studies of hsa-miR-155-5p were performed to confirm the role of hsa-miR-155-5p in the regulation of the SHIP1. We demonstrated that hsa-miR-155-5p modulates the proinflammatory response by activating the PI3K/AKT pathway through the inhibition of SHIP1 in SARS-CoV-2 ORF3a transfected human lung epithelial cells.


Assuntos
COVID-19 , Células Epiteliais , Pulmão , MicroRNAs , Fosfatidilinositol 3-Quinases , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Proteínas Proto-Oncogênicas c-akt , SARS-CoV-2 , Transdução de Sinais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol 3-Quinases/metabolismo , COVID-19/genética , COVID-19/virologia , COVID-19/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Pulmão/virologia , Pulmão/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Células A549
2.
Mol Neurobiol ; 61(3): 1807-1817, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37776496

RESUMO

Stroke is a life-threatening medical condition across the world that adversely affects the integrity of the blood-brain barrier (BBB). The brain microvascular endothelial cells are the important constituent of the BBB. These cells line the blood vessels and form a semipermeable barrier. Disruptions in adherens junction and tight junction proteins of brain microvascular endothelial cells compromise the integrity of BBB. The Vascular Endothelial (VE)-cadherin is an integral adherens junction protein required for the establishment and maintenance of the endothelial barrier integrity. This study aims to investigate the role of miRNA in hypoxia-induced endothelial barrier disruption. In this study, brain endothelial cells were exposed to hypoxic conditions for different time points. Western blotting, overexpression and knockdown of miRNA, real-time PCR, TEER, and sodium fluorescein assay were used to examine the effect of hypoxic conditions on brain endothelial cells. Hypoxic exposure was validated using HIF-1α protein. Exposure to hypoxic conditions resulted to a significant decrease in endothelial barrier resistance and an increase in sodium fluorescein migration across the endothelial barrier. Reduction in endothelial barrier resistance demonstrated compromised barrier integrity, whereas the increase in migration of sodium fluorescein across the barrier indicated the increase in barrier permeability. The present study revealed microRNA-101 decreases the expression of VE-cadherin and claudin-5 in brain endothelial cells exposed to the hypoxic conditions.


Assuntos
Antígenos CD , Células Endoteliais , MicroRNAs , Humanos , Células Endoteliais/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Fluoresceína/metabolismo , Fluoresceína/farmacologia , Caderinas/genética , Caderinas/metabolismo , Barreira Hematoencefálica/metabolismo , Hipóxia/metabolismo , MicroRNAs/metabolismo
3.
J Mycol Med ; 33(4): 101415, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37549615

RESUMO

Cryptococcus species are ingenious human pathogens that are widespread globally. They continue to cause over 200,000 deaths per year. Presently due to the rise in resistance and therapy failure, it is necessary to shift the focus to an alternate therapeutic strategy against this pathogen. One promising approach is to emphasize the host defense system in order to develop more precise and customized treatment strategies. In this regard, research has revealed that interferon-γ-inducible CXCL10 chemokine, amongst other chemokines spanning both CXC and CC categories, has a direct killing effect in vitro against Cryptococcus neoformans and Cryptococcus gattii, with a significantly greater microbicidal effect against the former. Moreover, when CXCL10 is used in combination with CCL5, there is a significant reduction in the survival of C. gattii at normal-serum level concentration, indicating a previously unreported synergistic effect of these two chemokines. Confocal and STED microscopic studies have demonstrated that CXCL10 has both cell wall/membrane and intracellular targets against this fungus. These findings present new possibilities for developing chemokine-derived small molecule antifungals and may represent a step forward in creating precision medicine tailored to each patient.


Assuntos
Anti-Infecciosos , Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Humanos , Quimiocina CXCL10/farmacologia , Interferon gama , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Anti-Infecciosos/farmacologia
4.
Microbes Infect ; 25(7): 105173, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37327858

RESUMO

Chandipura virus (CHPV) belongs to the family Rhabdoviridae and has a single-stranded RNA genome that causes encephalitis among children in India's tropical states. Activation of the antiviral immune response upon viral infection is important for the host's defense. In response to CHPV infection, the brain resident macrophages (microglial cells) control the pathogenic insults. The microRNAs (miRNAs) are 22 nts non-coding RNAs that serve as delicate regulators of their target genes at the post-transcriptional level. In this study, we explored miR-155 mediated antiviral response in CHPV infected human microglial cells. The gene and protein expression patterns were studied through quantitative real-time PCR (qPCR) and immunoblotting, respectively. Additionally, miRNA target validation was done by overexpression and knockdown of miR-155. We observed an increased expression of miR-155 in CHPV infected human microglial cells. The upregulated miR-155 suppresses the Suppressor of Cytokine Signalling 1 (SOCS1). Reduced SOCS1, in turn, led to enhanced phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and induction of Interferon-ß (IFN-ß), which promoted the expression of IFN-stimulated gene 54 (ISG54) and IFN-stimulated gene 56 (ISG56). In this study, miR-155 positively modulated the cellular antiviral response by enhancing type I IFN signalling through inhibition of SOCS1 in CHPV infected microglial cells.


Assuntos
MicroRNAs , Vesiculovirus , Criança , Humanos , Vesiculovirus/genética , Microglia , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais , Imunidade
5.
Cell Signal ; 106: 110659, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36948479

RESUMO

Zika virus infection has been reported to cause microcephaly in newborns. ZIKV exploits various strategies to cross the blood-brain barrier. ZIKV NS1 may compromise the barrier integrity of endothelial cells by regulating expression of junctional proteins. MicroRNAs play an important role in post-transcriptional gene regulations. We demonstrated that ZIKV-NS1 affected the adherence junction protein in human brain microvascular endothelial cells via hsa-miR-29b-3p/DNMT3b/MMP-9 pathway. The hCMEC/D3 cells were exposed to ZIKV-NS1 with different doses (500 ng/mL and 1000 ng/mL) for 24 h. The expression pattern of DNTM3b, MMP-9, and VE-cadherin were studied using immunoblotting and the distribution of DNMT3b and MMP-9 were studied using immunofluorescence. The quantification of hsa-miR-29b-3p was done through qRT-PCR. Direct regulation of DNMT3b by hsa-miR-29b-3p was demonstrated by overexpression of hsa-miR-29b-3p using hsa-miR-29b-3p mimic, and knockdown of hsa-miR-29b-3p by using hsa-miR-29b-3p inhibitors. The ZIKV-NS1 affected the barrier function of endothelial cells through the increased expression of hsa-miR29b-3p, which suppressed the DNMT3b, thus enhanced expression of MMP-9, which finally suppressed the expression of VE-cadherin. These findings suggested that ZIKV-NS1 alters the expression of Adherens Junction protein in human brain microvascular endothelial cells through hsa-miR-29b-3p/DNMT3b/MMP-9 pathway, which compromised the barrier function of human brain microvascular endothelial cells.


Assuntos
MicroRNAs , Infecção por Zika virus , Zika virus , Recém-Nascido , Humanos , Zika virus/genética , Zika virus/metabolismo , Células Endoteliais/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infecção por Zika virus/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Encéfalo/metabolismo
6.
J Med Virol ; 94(2): 480-490, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-31017674

RESUMO

Chandipura virus (CHPV) is a neurotropic virus, known to cause encephalitis in humans. The microRNAs (miRNA/miR) play an important role in the pathogenesis of viral infection. The present study is focused on the role of miRNAs during CHPV (strain 1653514) infection in human microglial cells. The deep sequencing of CHPV-infected human microglial cells identified a total of 12 differentially expressed miRNA (DEMs). To elucidate the role of DEMs, the target gene prediction, Gene Ontology term (GO Term), pathway enrichment analysis, and miRNA-messenger RNA (mRNA) interaction network analysis was performed. The GO terms and pathway enrichment analysis provided 146 enriched genes; which were involved in interferon response, cytokine and chemokine signaling. Further, the WGCNA (weighted gene coexpression network analysis) of the enriched genes were discretely categorized into three modules (blue, brown, and turquoise). The hub genes in the blue module may correlate to CHPV induced neuroinflammation. Altogether, the miRNA-mRNA interaction network and WGCNA study revealed the following pairs, hsa-miR-542-3p and FAF1, hsa-miR-92a-1-5p and MYD88, and hsa-miR-3187-3p and TNFRSF21, which may contribute to neuroinflammation during CHPV infection in human microglial cells.


Assuntos
Redes Reguladoras de Genes/genética , MicroRNAs/genética , Microglia/metabolismo , Vesiculovirus/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Humanos , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Doenças Neuroinflamatórias/genética , Doenças Neuroinflamatórias/virologia , Receptores do Fator de Necrose Tumoral/genética , Infecções por Rhabdoviridae/genética , Infecções por Rhabdoviridae/virologia
7.
Int J Biol Macromol ; 193(Pt B): 2290-2296, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34798192

RESUMO

Zika virus (ZIKV) is a positive-single strand RNA virus that belongs to the Flaviviridae family. ZIKV infection causes congenital ZIKV syndrome (CZS) in children and Guillain Barre Syndrome (GBS) in adults. ZIKV infected cells secrete non-structural protein 1 (sNS1), which plays an important role in viral replication and immune evasion. The microglial cells are the brain resident macrophages that mediate the immune responses in CNS. The miRNAs are small non-coding RNAs that regulate the expression of their target genes by binding to the 3'UTR region. The present study highlights the bystander effect of ZIKV-NS1 via miR-146a. The Real-Time PCR, Immunoblotting, overexpression, knockdown studies, and reactive oxygen species measurement have been done to study the immunomodulatory effects of ZIKV-NS1 in human microglial cells. ZIKV-NS1 induced the expression of miR-146a and suppressed the ROS activity in human microglial cells. The up-regulated miR-146a led to the decreased expression of TRAF6 and STAT-1. The reduced expression of TRAF6 in turn led to the suppression of pNF-κBp65 and TNF-α downstream. The miR-146a suppressed the pro-inflammatory and cellular antiviral responses in microglial cells. Our findings demonstrate the bystander role of ZIKV-NS1 in suppressing the pro-inflammatory and cellular antiviral responses through miR-146a in human microglial cells.


Assuntos
Imunidade Inata/imunologia , MicroRNAs/imunologia , Microglia/imunologia , Proteínas não Estruturais Virais/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Regiões 3' não Traduzidas/imunologia , Células Cultivadas , Citocinas/imunologia , Humanos , Microglia/virologia , RNA Mensageiro/imunologia , Transdução de Sinais/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Regulação para Cima/imunologia , Replicação Viral/imunologia , Infecção por Zika virus/virologia
8.
Mol Neurobiol ; 58(12): 6290-6303, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34487317

RESUMO

Zika virus (ZIKV) is a neurotropic virus that causes microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. ZIKV is known to transmigrate through the blood-brain barrier (BBB) by utilizing different strategies. NS1 is a conserved flavivirus protein, which is secreted extracellularly. ZIKV-NS1 has been shown to target adherens junctions (AJs) and tight junctions (TJs) to disrupt the endothelial barrier integrity. The microRNAs are short non-coding RNAs, which post-transcriptionally regulate the gene expression by binding to 3' UTR of the target gene. In the present study, we studied the ZIKV-NS1-mediated effect through hsa-miR-101-3p on the junctional barrier integrity in human brain microvascular endothelial cells. We exposed hBMVECs and hCMEC/D3 cells with ZIKV-NS1 at different time points (12 h and 24 h) with the doses 500 ng/mL and 1000 ng/mL. The change in the expression of VE-cadherin and claudin-5 was quantified using immunoblotting. The expression of the hsa-miR-101-3p was quantified using qRT-PCR. To prove the targeting of hsa-miR-101-3p to VE-cadherin, we transfected hsa-miR-101-3p mimic, scramble, hsa-miR-101-3p inhibitor, and Cy3 in the ZIKV-NS1-exposed hCMEC/D3 cells. The distribution and expression of the VE-cadherin and claudin-5 were observed using immunofluorescence and immunoblotting. The ZIKV-NS1 compromises the endothelial barrier integrity by disrupting the VE-cadherin and claudin-5 protein expression via hsa-miR-101-3p. The findings of this study suggest that ZIKV-NS1 dysregulates the adherens junction and tight junction proteins through hsa-miR-101-3p, which compromises the barrier integrity of human brain microvascular endothelial cells.


Assuntos
Antígenos CD/metabolismo , Encéfalo/metabolismo , Caderinas/metabolismo , Claudina-5/metabolismo , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Junções Aderentes/metabolismo , Encéfalo/virologia , Células Endoteliais/virologia , Humanos , Junções Íntimas/metabolismo , Zika virus
9.
J Biomed Sci ; 28(1): 52, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233673

RESUMO

BACKGROUND: Chandipura virus (CHPV) is a negative single-stranded RNA virus of the Rhabdoviridae family. CHPV infection has been reported in Central and Western India. CHPV causes acute encephalitis with a case fatality rate of 70 % and mostly affects children below 15 years of age. CHPV infection in brain leads to neuronal apoptosis and activation of the microglial cells. The microRNAs (miRNAs) are small endogenous non-coding RNA that regulate the gene expression. Viral infections perturb the expression pattern of cellular miRNAs, which may in turn affect the expression pattern of downstream genes. This study aims to investigate hsa-miR-21-5p mediated regulation of PTEN, AKT, NF-ĸBp65, IL-6, TNF-α, and IL-1ß, in human microglial cells during CHPV infection. METHODS: To understand the role of hsa-miR-21-5p in CHPV infection, the human microglial cells were infected with CHPV (MOI-0.1). Real-time PCR, western blotting, Luciferase assay, over-expression and knockdown techniques were used to understand the role of hsa-miR-21-5p in the regulation of PTEN, AKT and, NF-ĸBp65, IL-6, TNF-α, and IL-1ß in this study. RESULTS: The hsa-miR-21-5p was found to be upregulated during CHPV infection in human microglial cells. This led to the downregulation of PTEN which promoted the phosphorylation of AKT and NF-ĸBp65. Over-expression of hsa-miR-21-5p led to the decreased expression of PTEN and promoted further phosphorylation of AKT and NF-ĸBp65 in human microglial cells. However, the inhibition of hsa-miR-21-5p using hsa-miR-21-5p inhibitor restored the expression. CONCLUSIONS: This study supports the role of hsa-miR-21-5p in the regulation of pro-inflammatory genes in CHPV infected human microglial cells.


Assuntos
MicroRNAs/genética , Microglia/metabolismo , NF-kappa B/genética , Vesiculovirus/fisiologia , Humanos , MicroRNAs/metabolismo , NF-kappa B/metabolismo
10.
Virology ; 560: 86-95, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051478

RESUMO

Zika virus (ZIKV) is a mosquito-borne neurotropic flavivirus. ZIKV infection may lead to microcephaly in developing fetus and Guillain-Barré Syndrome (GBS) like symptoms in adults. ZIKV was first reported in humans in 1952 from Uganda and the United Republic of Tanzania. Later, ZIKV outbreak was reported in 2007 from the Yap Island. ZIKV re-emerged as major outbreak in the year 2013 from French Polynesia followed by second outbreak in the year 2015 from Brazil. ZIKV crosses the blood-tissue barriers to enter immune-privileged organs. Clinical manifestations in ZIKV disease includes rash, fever, conjunctivitis, muscle and joint pain, headache, transverse myelitis, meningoencephalitis, Acute Disseminated Encephalomyelitis (ADEM). The understanding of the molecular mechanism of ZIKV pathogenesis is very important to develop potential diagnostic and therapeutic interventions for ZIKV infected patients.


Assuntos
Encefalomielite Aguda Disseminada/virologia , Meningoencefalite/virologia , Infecção por Zika virus/patologia , Infecção por Zika virus/transmissão , Zika virus/imunologia , Animais , Culicidae/virologia , Encefalomielite Aguda Disseminada/patologia , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Meningoencefalite/patologia , Placenta/virologia , Gravidez , Doenças Transmitidas por Vetores/virologia , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidade
11.
Sci Total Environ ; 773: 145525, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940729

RESUMO

Airborne transmission is one of the routes for the spread of COVID-19 which is caused by inhalation of smaller droplets1 containing SARS-CoV-2 (i.e., either virus-laden particulate matter: PM and/or droplet nuclei) in an indoor environment. Notably, a significant fraction of the small droplets, along with respiratory droplets, is produced by both symptomatic and asymptomatic individuals during expiratory events such as breathing, sneezing, coughing and speaking. When these small droplets are exposed to the ambient environment, they may interact with PM and may remain suspended in the atmosphere even for several hours. Therefore, it is important to know the fate of these droplets and processes (e.g., physical and chemical) in the atmosphere to better understand airborne transmission. Therefore, we reviewed existing literature focussed on the transmission of SARS-CoV-2 in the spread of COVID-19 and present an environmental perspective on why airborne transmission hasn't been very conclusive so far. In addition, we discuss various environmental factors (e.g., temperature, humidity, etc.) and sampling difficulties, which affect the conclusions of the studies focussed on airborne transmission. One of the reasons for reduced emphasis on airborne transmission could be that the smaller droplets have less number of viruses as compared to larger droplets. Further, smaller droplets can evaporate faster, exposing SARS-CoV-2 within the small droplets to the environment, whose viability may further reduce. For example, these small droplets containing SARS-CoV-2 might also physically combine with or attach to pre-existing PM so that their behaviour and fate may be governed by PM composition. Thus, the measurement of their infectivity and viability is highly uncertain due to a lack of robust sampling system to separately collect virions in the atmosphere. We believe that the present review will help to minimize the gap in our understanding of the current pandemic and develop a robust epidemiological method for mortality assessment.


Assuntos
COVID-19 , Tosse , Expiração , Humanos , Umidade , SARS-CoV-2
12.
Respir Res ; 21(1): 318, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261606

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) belongs to the group of Betacoronaviruses. The SARS-CoV-2 is closely related to SARS-CoV-1 and probably originated either from bats or pangolins. SARS-CoV-2 is an etiological agent of COVID-19, causing mild to severe respiratory disease which escalates to acute respiratory distress syndrome (ARDS) or multi-organ failure. The virus was first reported from the animal market in Hunan, Hubei province of China in the month of December, 2019, and was rapidly transmitted from animal to human and human-to-human. The human-to-human transmission can occur directly or via droplets generated during coughing and sneezing. Globally, around 53.9 million cases of COVID-19 have been registered with 1.31 million confirmed deaths. The people > 60 years, persons suffering from comorbid conditions and immunocompromised individuals are more susceptible to COVID-19 infection. The virus primarily targets the upper and the lower respiratory tract and quickly disseminates to other organs. SARS-CoV-2 dysregulates immune signaling pathways which generate cytokine storm and leads to the acute respiratory distress syndrome and other multisystemic disorders.


Assuntos
COVID-19/virologia , Genoma Viral , SARS-CoV-2/genética , Animais , Antivirais/uso terapêutico , COVID-19/imunologia , COVID-19/terapia , COVID-19/transmissão , Vacinas contra COVID-19/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Prognóstico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Zoonoses Virais , Tratamento Farmacológico da COVID-19
13.
Biochimie ; 176: 52-61, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32640279

RESUMO

Zika virus (ZIKV) infection leads to microcephaly in newborns. Flaviviruses are known to secrete NS1 protein extracellularly and its concentration in serum directly co-relate to disease severity. The presence of ZIKV-NS1 near the brain microvascular endothelial cells (BMVECs) affects blood-brain-barrier, which is composed of tight junctions (TJs) and adherens junctions (AJs). Viruses utilize different strategies to circumvent this barrier to enter in brain. The present study demonstrated the mechanism of junctional integrity disruption in BMVECs by ZIKV-NS1 protein exposure. The Transendothelial Electrical Resistance and sodium fluorescein migration assays revealed the endothelial barrier disruption in BMVECs exposed to ZIKV-NS1 at different time (12hr and 24hr) and doses (500 ng/mL, 1000 ng/mL and 1500 ng/mL). The exposure of ZIKV-NS1 on BMVECs led to the phosphorylation of AJs and suppression of TJs through secreted ZIKV-NS1 in a bystander fashion. The activation of NADPH dependent reactive oxygen species activity and redox sensitive tyrosine kinase further increased the phosphorylation of AJs. The reduced expression of the phosphatase led to the increased phosphorylation of the AJs. The treatment with Diphenyleneiodonium chloride rescued the phosphatase and TJs expression and suppressed the expression of kinase and AJs in BMVECs exposed to ZIKV-NS1.


Assuntos
Junções Aderentes/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Microvasos/metabolismo , Junções Íntimas/metabolismo , Proteínas não Estruturais Virais/metabolismo , Zika virus/metabolismo , Humanos , Proteínas não Estruturais Virais/farmacologia
15.
J Med Virol ; 92(2): 139-148, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31483508

RESUMO

Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes. CHIKV infection leads to polyarthritis and polyarthralgia among patients. The synovial fibroblasts are the primary target for CHIKV. The microRNAs (miRNAs) are the small endogenous noncoding RNAs which posttranscriptionally regulate the expression of genes by binding to their target messenger RNAs (mRNAs) through their 3'-untranslated regions. The miRNAs are the key regulators for various pathological processes including viral infection, cancer, cardiovascular disease, and neurodegeneration. This study was designed to dissect out the roles of miRNAs during CHIKV (Ross Strain E1: A226V) infection in primary human synovial fibroblasts. The miRNA microarray profiling was performed on the primary human synovial fibroblasts infected by CHIKV. The gene target prediction analysis, enrichment, and network analysis were performed by various bioinformatics analyses. The subset of 26 differentially expressed microRNAs (DEMs) were identified through microarray profiling and were further screened for gene predictions, Gene Ontology, pathway enrichment, and miRNA-mRNA network using various bioinformatics tools. The bioinformatics analysis indicates the role of DEMs by suppressing the immune response which may contribute to CHIKV persistence in human primary synovial fibroblasts. Our study provides the plausible roles of DEMs, miRNAs, and mRNA interactions and pathways involved in the molecular pathogenesis of CHIKV.


Assuntos
Febre de Chikungunya/genética , Fibroblastos/virologia , MicroRNAs/genética , RNA Mensageiro/genética , Animais , Células Cultivadas , Vírus Chikungunya/patogenicidade , Chlorocebus aethiops , Biologia Computacional , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Análise em Microsséries , Membrana Sinovial/virologia , Células Vero
16.
Artigo em Inglês | MEDLINE | ID: mdl-31448245

RESUMO

Japanese Encephalitis virus (JEV) is a neurotropic ssRNA virus, belonging to the Flaviviridae family. JEV is one of the leading causes of the viral encephalitis in Southeast-Asian countries. JEV primarily infects neurons however, the microglial activation has been reported to further enhance the neuroinflammation and promote neuronal death. The PI3K/AKT pathway has been reported to play an important role in type-I interferon response via IRF3. Phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/AKT pathway, participates in microglial polarization and neuroinflammation. The microRNAs are small non-coding endogenously expressed RNAs, which regulate the gene expression by binding at 3' UTR of target gene. The human microglial cells were infected with JEV (JaOArS982 strain) and up-regulation of microRNA; hsa-miR-374b-5p was confirmed by qRT-PCR. The genes in PI3K/AKT pathway, over-expression and knock-down studies of hsa-miR-374b-5p with and without JEV infection were analyzed through immuno blotting. The regulatory role of hsa-miR-374b-5p on the expression of type-I interferon was determined by luciferase assays. JEV infection modulated the expression of hsa-miR-374b-5p and PI3K/AKT pathway via PTEN. The over-expression of hsa-miR-374b-5p suppressed the PTEN while up-regulated the AKT and IRF3 proteins, whereas, the knockdown rescued the PTEN expression and suppressed the AKT and IRF3 proteins. The modulation of hsa-miR-374b-5p regulated the type-I interferon response during JEV infection. In present study, we have shown the modulation of PTEN by hsa-miR-374b-5p, which regulated the PI3K/AKT/IRF3 axis in JEV infected microglial cells.


Assuntos
Vírus da Encefalite Japonesa (Espécie)/fisiologia , Encefalite Japonesa/genética , Encefalite Japonesa/virologia , Interações Hospedeiro-Patógeno/genética , Interferon Tipo I/genética , MicroRNAs/genética , Microglia/metabolismo , Microglia/virologia , Animais , Células Cultivadas , Encefalite Japonesa/metabolismo , Humanos , Interferon Tipo I/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
17.
J Med Virol ; 90(4): 648-654, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29149532

RESUMO

JEV infection in CNS leads to the JE neuroinflammation. Children and old age individual have been reported to be more prone to JEV infection. MicroRNAs are endogenous, small non-coding RNAs, which regulate the gene expression. These are ∼22 nucleotide long, conserved RNA sequence that binds at the 3'UTR of a target mRNA and regulate the post-transcriptional gene expression. The role of microRNAs has been reported in several diseases like cancer, viral infection, neuro-degeneration, diabetes etc. In the present study, the human microglial cells were infected with JEV (JaOArS982). The control and infected samples were subject to microarray profiling for microRNA expression. The microarray profile yielded differentially expressed microRNAs from JEV infected samples. The microRNA gene targets, gene ontology, annotations, and pathways were identified through various bioinformatics tools. Additionally, the pathways were mostly found common to "ubiquitin mediated proteolysis," "cytokine signaling," "maintenance of barrier function/cell junctions," JAK/STAT pathway" "Toll-like receptor signaling," "Wnt-signaling," "adhesion molecules," "apoptosis," "endocytosis," "vesicle mediated transport" etc.


Assuntos
Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/patologia , Interações Hospedeiro-Patógeno , MicroRNAs/metabolismo , Neuroglia/virologia , Células Cultivadas , Encefalite Japonesa/virologia , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Análise em Microsséries , Modelos Biológicos
18.
Curr HIV Res ; 14(5): 382-388, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27719664

RESUMO

HIV infection among AIDS patients is associated with dysfunctions in the central nervous system (CNS) at the late stages of the disease. HIV Tat protein is released extracellularly from the productively infected cells and play important role in successful HIV replication and activates the neighboring uninfected cells in the bystander fashion. The structural flexibility of Tat protein is one of the unique features, responsible for the diverse functions. The RNA binding ability and interacting domains are very important characteristic of the HIV-Tat protein. HIV Tat protein adversely affects the integrity of the blood brain barrier by a variety of mechanisms. Such compromise in the integrity of the blood brain barrier could affect the neuro-immune interactions within the brain, which results to the neuroinflammation.


Assuntos
Complexo AIDS Demência/fisiopatologia , Complexo AIDS Demência/virologia , Barreira Hematoencefálica/fisiologia , Barreira Hematoencefálica/virologia , Interações Hospedeiro-Patógeno , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Humanos
20.
Semin Respir Crit Care Med ; 37(4): 572-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27486737

RESUMO

Coronaviruses (CoVs) are enveloped RNA viruses that infect birds, mammals, and humans. Infections caused by human coronaviruses (hCoVs) are mostly associated with the respiratory, enteric, and nervous systems. The hCoVs only occasionally induce lower respiratory tract disease, including bronchitis, bronchiolitis, and pneumonia. In 2002 to 2003, a global outbreak of severe acute respiratory syndrome (SARS) was the seminal detection of a novel CoV (SARS-CoV). A decade later (June 2012), another novel CoV was implicated as the cause of Middle East respiratory syndrome (MERS) in Saudi Arabia. Although bats might serve as a reservoir of MERS-CoV, it is unlikely that they are the direct source for most human cases. Severe lines of evidence suggest that dromedary camels have been the major cause of transmission to humans. The emergence of MERS-CoV has triggered serious concerns about the potential for a widespread outbreak. All MERS cases were linked directly or indirectly to the Middle East region including Saudi Arabia, Jordan, Qatar, Oman, Kuwait, and UAE. MERS cases have also been reported in the later phases in the United Kingdom, France, Germany, Italy, Spain, and Tunisia. Most of these MERS cases were linked with the Middle East. The high mortality rates in family-based and hospital-based outbreaks were reported among patients with comorbidities such as diabetes and renal failure. MERS-CoV causes an acute, highly lethal pneumonia and renal dysfunction. The major complications reported in fatal cases are hyperkalemia with associated ventricular tachycardia, disseminated intravascular coagulation, pericarditis, and multiorgan failure. The case-fatality rate seems to be higher for MERS-CoV (around 30%) than for SARS-CoV (9.6%). The combination regimen of type 1 interferon + lopinavir/ritonavir is considered as the first-line therapy for MERS. Antiviral treatment is generally recommended for 10 to 14 days in patients with MERS-CoV infection. Convalescent plasma therapy has shown some efficacy among patients refractory to antiviral drugs if administered within 2 weeks of the onset of the disease.


Assuntos
Infecções por Coronavirus/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio , Síndrome Respiratória Aguda Grave/virologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Animais , Camelus/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/transmissão , Humanos , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/transmissão
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