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1.
Cell Rep ; 42(8): 112977, 2023 08 29.
Artículo en Inglés | MEDLINE | ID: mdl-37573505

RESUMEN

Arthropod-borne viruses (arboviruses) transmitted by Aedes aegypti mosquitoes are an increasing threat to global health. The small interfering RNA (siRNA) pathway is considered the main antiviral immune pathway of insects, but its effective impact on arbovirus transmission is surprisingly poorly understood. Here, we use CRISPR-Cas9-mediated gene editing in vivo to mutate Dicer2, a gene encoding the RNA sensor and key component of the siRNA pathway. The loss of Dicer2 enhances early viral replication and systemic viral dissemination of four medically significant arboviruses (chikungunya, Mayaro, dengue, and Zika viruses) representing two viral families. However, Dicer2 mutants and wild-type mosquitoes display overall similar levels of vector competence. In addition, Dicer2 mutants undergo significant virus-induced mortality during infection with chikungunya virus. Together, our results define a multifaceted role for Dicer2 in the transmission of arboviruses by Ae. aegypti mosquitoes and pave the way for further mechanistic investigations.


Asunto(s)
Aedes , Arbovirus , Infección por el Virus Zika , Virus Zika , Animales , Humanos , Arbovirus/genética , Arbovirus/metabolismo , Mosquitos Vectores , Virus Zika/genética , ARN Interferente Pequeño/metabolismo
2.
J Mol Biol ; 434(6): 167277, 2022 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-34599939

RESUMEN

Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions induced by IFN. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent manner, opening new perspectives to target weakness points in the life cycle of these viruses.


Asunto(s)
Flavivirus , Interferones , Replicación Viral , Apolipoproteínas L/genética , Apolipoproteínas L/metabolismo , Flavivirus/fisiología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Interferones/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , SARS-CoV-2/fisiología , Virus Zika/fisiología
3.
Virologie (Montrouge) ; 23(3): 160-175, 2019 06 01.
Artículo en Francés | MEDLINE | ID: mdl-31210133

RESUMEN

The replication of viral pathogens relies on their ability to manipulate their host. Several steps of the infectious cycle require the hijacking of cellular membranes. Positive stranded RNA viruses replicating in the cytoplasm of their host reorganize cellular membranes. This leads to the formation of organelles, which host viral replication. The formation of such compartments, which are genuine viral factories, induces morphological modifications of the host cell, which vary depending on the pathogen. However, the molecular mechanisms underlying such a remodeling remain unclear. These mechanisms are subject to intense research since their formation is indispensable to viral multiplication and therefore represent an attractive therapeutic target. In this review, we provide a bird's eye view on the current knowledge of the architecture and virus-host interactions involved in the biogenesis of positive stranded RNA virus replication organelles.


Asunto(s)
Orgánulos , Virus ARN Monocatenarios Positivos , Interacciones Microbiota-Huesped , ARN , Replicación Viral/genética
4.
Eur J Dermatol ; 27(6): 579-589, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29171393

RESUMEN

In psoriasis, a specific cytokine network has been described to play a central role in the pathophysiology of the disease. Anti-cytokine therapeutic approaches have been largely developed and TNFα constitutes the main target. Adalimumab is a human anti-TNFα monoclonal antibody that has been reported to demonstrate clinical efficacy and safety, resulting in reversal of epidermal hyperplasia and cutaneous inflammation. We aimed to analyse changes in the skin inflammatory transcriptomic profile in psoriatic patients during adalimumab therapy. In addition, the circulating cytokine profile was analysed to define systemic inflammation. Eighteen patients with chronic plaque psoriasis were treated with adalimumab. After four and 16 weeks, clinical efficacy was assessed using PASI and DLQI, and skin mRNA profiles were determined and circulating cytokines quantified. We identified a rapid effect of adalimumab therapy on a large array of Th17 cytokines of the skin, which may account for the modification of keratinocyte expression profile and clinical response. In contrast, analysis of serum cytokine concentrations was uninformative, confirming the need for characterization of local cytokines in skin lesions. Finally, in non-responders, local cytokine expression was shown to be unchanged. We show that TNFα inhibition in psoriasis patients treated with adalimumab has a broad effect on the expression profile of cytokines and keratinocyte markers of skin inflammation, which may account for its clinical efficacy.


Asunto(s)
Adalimumab/uso terapéutico , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Piel/inmunología , Anticuerpos Monoclonales , Terapia Biológica , Perfilación de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , Psoriasis/metabolismo , ARN Largo no Codificante , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Piel/metabolismo , Estadísticas no Paramétricas , Células Th17 , Resultado del Tratamiento
5.
PLoS One ; 12(7): e0181486, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28708859

RESUMEN

BACKGROUND: Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPß, STAT3 activated by proinflammatory cytokines. OBJECTIVES: We investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients. METHODS: NHEK were stimulated by A-SAA or the cytokines IL-1α, IL-17A, IL-22, OSM, TNF-α alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay. RESULTS: IL-1α, TNF-α and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed. CONCLUSION: Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.


Asunto(s)
Dermatitis Atópica/patología , Interleucina-17/farmacología , Psoriasis/patología , Proteína Amiloide A Sérica/metabolismo , Piel/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Adulto , Anciano , Aminoquinolinas/farmacología , Animales , Células Cultivadas , Quimiocina CCL20/metabolismo , Quimiocina CCL20/farmacología , Citocinas/genética , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Imiquimod , Interleucina-17/genética , Interleucina-17/metabolismo , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Psoriasis/metabolismo , Receptores CCR6/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , Proteína Amiloide A Sérica/análisis , Proteína Amiloide A Sérica/genética , Piel/metabolismo , Células Th17/citología , Células Th17/metabolismo
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