Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 172
Filtrar
Más filtros













Base de datos
Intervalo de año de publicación
1.
Nat Commun ; 15(1): 4096, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38750019

RESUMEN

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.


Asunto(s)
Viroterapia Oncolítica , Virus Oncolíticos , Succinatos , Animales , Humanos , Viroterapia Oncolítica/métodos , Succinatos/farmacología , Ratones , Línea Celular Tumoral , Interferón Tipo I/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias del Colon/terapia , Neoplasias del Colon/inmunología , Neoplasias del Colon/tratamiento farmacológico , Antivirales/farmacología , FN-kappa B/metabolismo , Quinasa I-kappa B/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Inflamación/tratamiento farmacológico , Femenino , Virus de la Estomatitis Vesicular Indiana/fisiología , Virus de la Estomatitis Vesicular Indiana/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
2.
Immun Inflamm Dis ; 12(1): e1154, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38270301

RESUMEN

INTRODUCTION: Neutralizing antibodies (NAbs) are an important specific defence against viral infections, as these antibodies bind to specific receptor(s) and block the viral entry. NAbs assessments are therefore useful in determining individual or herd immunity to SARS-CoV-2. This study aims to deepen the investigation by assessing the positivity rate of neutralizing anti-spike antibodies to understand the real protection of the studied population against SARS-CoV-2. METHODS: This study involved 260 plasma samples from a larger cohort of 2,700 asymptomatic volunteer donors, enrolled between August and October 2021 in health facilities of N'Djamena. In this study four different kits and techniques including the pseudotype assay have been used and compared with detect the SARS-CoV-2 antibodies. Pseudotyped vesicular stomatitis virus (VSV), was used both the identify and measure the NAbs that to evaluate the performance of two cheaper and easy to use commercial kits, specific for the detection of receptor-binding domain antibodies (anti-RBD) against the SARS-CoV-2 spike protein. RESULTS: The VSV spike neutralization assay showed that 59.0% (n = 59) samples were positive for NAbs with titers ranging from 1:10 to 1:4800. While 23 out the 41 negative NAbs samples were detected positive using anti-RBD (Abbott) test. Furthermore, a direct and significant strong correlation was found between NAbs and anti-RBD, specifically with Abbott kit. Taken together, the Roche and Abbott methods indicated agreement at the high concentrations of antibodies with the VSV-pseudovirus method. Abbott and Roche indicated a good sensitivity, but the Abbott system test appeared to have better specificity than the Roche test. CONCLUSION: Our findings indicated a high presence of NAbs against SARS-CoV-2 spike protein among asymptomatic individuals in N'Djamena. This could be one of the reasons for the low severity of Covid-19 observed in this area, given the key role of NAbs in blocking SARS-CoV-2 infection.


Asunto(s)
COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Chad , COVID-19/epidemiología , Anticuerpos Antivirales , Anticuerpos Neutralizantes
3.
Int J Mol Sci ; 24(13)2023 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-37445672

RESUMEN

There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164, were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-ß expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Interferón Tipo I , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Interferón Tipo I/metabolismo , Proteínas no Estructurales Virales/metabolismo , Gripe Humana/tratamiento farmacológico , Virus de la Influenza A/genética , Antivirales/farmacología , Antivirales/metabolismo , Replicación Viral
4.
Cancer Immunol Immunother ; 72(9): 3097-3110, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37356050

RESUMEN

Although the activation of innate immunity to treat a wide variety of cancers is gaining increasing attention, it has been poorly investigated in human papillomavirus (HPV)-associated malignancies. Because these tumors harbor a severely impaired cGAS-STING axis, but they still retain a largely functional RIG-I pathway, another critical mediator of adaptive and innate immune responses, we asked whether RIG-I activation by the 5'ppp-RNA RIG-I agonist M8 would represent a therapeutically viable option to treat HPV+ cancers. Here, we show that M8 transfection of two cervical carcinoma-derived cell lines, CaSki and HeLa, both expressing a functional RIG-I, triggers intrinsic apoptotic cell death, which is significantly reduced in RIG-I KO cells. We also demonstrate that M8 stimulation potentiates cisplatin-mediated cell killing of HPV+ cells in a RIG-I dependent manner. This combination treatment is equally effective in reducing tumor growth in a syngeneic pre-clinical mouse model of HPV16-driven cancer, where enhanced expression of lymphocyte-recruiting chemokines and cytokines correlated with an increased number of activated natural killer (NK) cells in the tumor microenvironment. Consistent with a role of RIG-I signaling in immunogenic cell killing, stimulation of NK cells with conditioned medium from M8-transfected CaSki boosted NK cell proliferation, activation, and migration in a RIG-I-dependent tumor cell-intrinsic manner. Given the highly conserved molecular mechanisms of carcinogenesis and genomic features of HPV-driven cancers and the remarkably improved prognosis for HPV+ oropharyngeal cancer, targeting RIG-I may represent an effective immunotherapeutic strategy in this setting, favoring the development of de-escalating strategies.


Asunto(s)
Neoplasias , Infecciones por Papillomavirus , Femenino , Humanos , Animales , Ratones , Virus del Papiloma Humano , Cisplatino/farmacología , Infecciones por Papillomavirus/complicaciones , Apoptosis , Células Asesinas Naturales
6.
Curr Opin Immunol ; 82: 102302, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36921380
7.
Methods Mol Biol ; 2589: 379-399, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36255638

RESUMEN

Oncolytic virotherapy represents an efficient immunotherapeutic approach for cancer treatment. Oncolytic viruses (OVs) promote antitumor responses through tumor-selective cell lysis and immune system activation. However, some tumor cell lines and primary tumors display resistance to therapy. Here we describe a protocol to identify novel host factors responsible for tumor resistance to oncolysis using an unbiased genome-wide CRISPR-Cas9 loss-of-function screening. Cas9-expressing tumor cells are transduced with a library of pooled single-guide RNA (sgRNA)-expressing lentiviruses that target all human genes to obtain a cell population where each cell is knocked out for a single gene. Upon OV infection, resistant cells survive, while sensitive cells die. The relative abundance of each genome-integrated sgRNA is measured by next-generation sequencing (NGS) in resistant and control cells. This protocol is amenable to uncover host factors involved in the resistance to different OVs in multiple tumor models.


Asunto(s)
Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Sistemas CRISPR-Cas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/genética , Neoplasias/terapia , Virus Oncolíticos/genética , ARN Guía de Sistemas CRISPR-Cas/genética
8.
Front Cell Infect Microbiol ; 12: 910864, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35923800

RESUMEN

Dendritic cells (DCs) are important mediators of the induction and regulation of adaptive immune responses following microbial infection and inflammation. Sensing environmental danger signals including viruses, microbial products, or inflammatory stimuli by DCs leads to the rapid transition from a resting state to an activated mature state. DC maturation involves enhanced capturing and processing of antigens for presentation by major histocompatibility complex (MHC) class I and class II, upregulation of chemokines and their receptors, cytokines and costimulatory molecules, and migration to lymphoid tissues where they prime naive T cells. Orchestrating a cellular response to environmental threats requires a high bioenergetic cost that accompanies the metabolic reprogramming of DCs during activation. We previously demonstrated that DCs undergo a striking functional transition after stimulation of the retinoic acid-inducible gene I (RIG-I) pathway with a synthetic 5' triphosphate containing RNA (termed M8), consisting of the upregulation of interferon (IFN)-stimulated antiviral genes, increased DC phagocytosis, activation of a proinflammatory phenotype, and induction of markers associated with immunogenic cell death. In the present study, we set out to determine the metabolic changes associated with RIG-I stimulation by M8. The rate of glycolysis in primary human DCs was increased in response to RIG-I activation, and glycolytic reprogramming was an essential requirement for DC activation. Pharmacological inhibition of glycolysis in monocyte-derived dendritic cells (MoDCs) impaired type I IFN induction and signaling by disrupting the TBK1-IRF3-STAT1 axis, thereby countering the antiviral activity induced by M8. Functionally, the impaired IFN response resulted in enhanced viral replication of dengue, coronavirus 229E, and Coxsackie B5.


Asunto(s)
Antivirales , Células Dendríticas , Antivirales/metabolismo , Glucólisis , Humanos , Monocitos , Tretinoina/metabolismo
9.
Cytokine Growth Factor Rev ; 63: 1-9, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35216872

RESUMEN

Since the beginning of the COVID-19 pandemic in 2019-2020, Cytokine & Growth Factor Reviews has published several Special Issues focused on the biology, pathogenesis and therapeutic options in the treatment of COVID-19 infection, including articles on the involvement of the chemokine system in the cytokine storm in COVID-19, intervention in the early stages of COVID-19 pneumonia, the therapeutic value of corticosteroid treatment, early clinical intervention with type 1 interferons, progress in vaccine development, and organ specific complications of COVID-19. By 2022, multiple highly efficacious vaccines are available and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become the most thoroughly studied virus in history. But, with progress has also come unanticipated problems - misinformation, anti-vaxxers, opposition to protective masks, and politically motivated interference disguised as knowledge. With this issue of CGFR, we continue to document the global coronavirus pandemic and provide an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment.


Asunto(s)
COVID-19 , Vacunas , COVID-19/prevención & control , Vacunas contra la COVID-19/uso terapéutico , Humanos , Pandemias/prevención & control , SARS-CoV-2
10.
Front Cell Infect Microbiol ; 12: 1079926, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36590581

RESUMEN

Virus-Like Particles (VLPs) are nanostructures that share conformation and self-assembly properties with viruses, but lack a viral genome and therefore the infectious capacity. In this study, we produced VLPs by co-expression of VSV glycoprotein (VSV-G) and HIV structural proteins (Gag, Pol) that incorporated a strong sequence-optimized 5'ppp-RNA RIG-I agonist, termed M8. Treatment of target cells with VLPs-M8 generated an antiviral state that conferred resistance against multiple viruses. Interestingly, treatment with VLPs-M8 also elicited a therapeutic effect by inhibiting ongoing viral replication in previously infected cells. Finally, the expression of SARS-CoV-2 Spike glycoprotein on the VLP surface retargeted VLPs to ACE2 expressing cells, thus selectively blocking viral infection in permissive cells. These results highlight the potential of VLPs-M8 as a therapeutic and prophylactic vaccine platform. Overall, these observations indicate that the modification of VLP surface glycoproteins and the incorporation of nucleic acids or therapeutic drugs, will permit modulation of particle tropism, direct specific innate and adaptive immune responses in target tissues, and boost immunogenicity while minimizing off-target effects.


Asunto(s)
COVID-19 , Interferón Tipo I , Vacunas de Partículas Similares a Virus , Virosis , Humanos , SARS-CoV-2 , Linfocitos T CD8-positivos , Vacunas de Partículas Similares a Virus/genética
11.
Pathogens ; 10(11)2021 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-34832672

RESUMEN

Despite the success of highly active antiretroviral therapy (HAART), integrated HIV-1 proviral DNA cannot be eradicated from an infected individual. HAART is not able to eliminate latently infected cells that remain invisible to the immune system. Viral sanctuaries in specific tissues and immune-privileged sites may cause residual viral replication that contributes to HIV-1 persistence. The "Shock or Kick, and Kill" approach uses latency reversing agents (LRAs) in the presence of HAART, followed by cell-killing due to viral cytopathic effects and immune-mediated clearance. Different LRAs may be required for the in vivo reactivation of HIV-1 in different CD4+ T cell reservoirs, leading to the activation of cellular transcription factors acting on the integrated proviral HIV-1 LTR. An important requirement for LRA drugs is the reactivation of viral transcription and replication without causing a generalized immune activation. Toll-like receptors, RIG-I like receptors, and STING agonists have emerged recently as a new class of LRAs that augment selective apoptosis in reactivated T lymphocytes. The challenge is to extend in vitro observations to HIV-1 positive patients. Further studies are also needed to overcome the mechanisms that protect latently infected cells from reactivation and/or elimination by the immune system. The Block and Lock alternative strategy aims at using latency promoting/inducing agents (LPAs/LIAs) to block the ability of latent proviruses to reactivate transcription in order to achieve a long term lock down of potential residual virus replication. The Shock and Kill and the Block and Lock approaches may not be only alternative to each other, but, if combined together (one after the other), or given all at once [namely "Shoc-K(kill) and B(block)-Lock"], they may represent a better approach to a functional cure.

12.
ACS Infect Dis ; 7(11): 3034-3051, 2021 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-34658235

RESUMEN

The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.


Asunto(s)
COVID-19 , SARS-CoV-2 , Antivirales/farmacología , Antivirales/uso terapéutico , Atovacuona/farmacología , Humanos , Estados Unidos
13.
Biology (Basel) ; 10(9)2021 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-34571706

RESUMEN

Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host-virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.

14.
Cytokine Growth Factor Rev ; 59: 1-8, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33610464

RESUMEN

During the Tenth Edition of the Annual Congress on "Anticancer Innovative Therapy" [Milan, 23/24 January 2020], experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i] epigenetics, and in particular, chromatin modifiers, ii] cancer metabolism, iii] cancer stem cells [CSCs], iv] tumor cell signaling, and iv] the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell-based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term.


Asunto(s)
Aniversarios y Eventos Especiales , Terapias en Investigación , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas
15.
Front Cell Infect Microbiol ; 11: 804976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35071051

RESUMEN

Influenza virus infection induces oxidative stress in host cells by decreasing the intracellular content of glutathione (GSH) and increasing reactive oxygen species (ROS) level. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for the production of reducing equivalents of nicotinamide adenine dinucleotide phosphate (NADPH) that is used to regenerate the reduced form of GSH, thus restoring redox homeostasis. Cells deficient in G6PD display elevated levels of ROS and an increased susceptibility to viral infection, although the consequences of G6PD modulation during viral infection remain to be elucidated. In this study, we demonstrated that influenza virus infection decreases G6PD expression and activity, resulting in an increase in oxidative stress and virus replication. Moreover, the down regulation of G6PD correlated with a decrease in the expression of nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor that regulates the expression of the antioxidant response gene network. Also down-regulated in influenza virus infected cells was sirtuin 2 (SIRT2), a NADPH-dependent deacetylase involved in the regulation of G6PD activity. Acetylation of G6PD increased during influenza virus infection in a manner that was strictly dependent on SIRT2 expression. Furthermore, the use of a pharmacological activator of SIRT2 rescued GSH production and NRF2 expression, leading to decreased influenza virus replication. Overall, these data identify a novel strategy used by influenza virus to induce oxidative stress and to favor its replication in host cells. These observations furthermore suggest that manipulation of metabolic and oxidative stress pathways could define new therapeutic strategies to interfere with influenza virus infection.


Asunto(s)
Glucosafosfato Deshidrogenasa , Orthomyxoviridae , Glucosafosfato Deshidrogenasa/genética , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno
17.
Nat Commun ; 11(1): 4938, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009401

RESUMEN

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.


Asunto(s)
Antiinflamatorios/farmacología , Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Dimetilfumarato/agonistas , Factor 2 Relacionado con NF-E2/metabolismo , Neumonía Viral/tratamiento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacología , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/virología , Dimetilfumarato/farmacología , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Interferón Tipo I , Pulmón/patología , Masculino , Factor 2 Relacionado con NF-E2/genética , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Transducción de Señal/efectos de los fármacos , Succinatos/farmacología , Replicación Viral/efectos de los fármacos
18.
J Virol ; 94(24)2020 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-32999020

RESUMEN

Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection.IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.


Asunto(s)
Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Células A549 , Línea Celular , Dengue/virología , Virus del Dengue/genética , Regulación Viral de la Expresión Génica , Técnicas de Inactivación de Genes , Células HEK293 , Hemo-Oxigenasa 1/genética , Humanos , Interferones , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno , Transducción de Señal/efectos de los fármacos
20.
PLoS Pathog ; 16(9): e1008855, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32986788

RESUMEN

SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.


Asunto(s)
Infecciones por Citomegalovirus/virología , Citomegalovirus/patogenicidad , Infecciones por Herpesviridae/metabolismo , Proteína 1 que Contiene Dominios SAM y HD/genética , Antivirales/farmacología , Quinasas Ciclina-Dependientes/metabolismo , Citomegalovirus/genética , Citoplasma/metabolismo , Citoplasma/virología , Humanos , Proteínas de Unión al GTP Monoméricas/metabolismo , Fosforilación , Replicación Viral/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA