ABSTRACT
SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.
ABSTRACT
Arsenic trioxide (AsO) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of AsO induced apoptosis of pDCs mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, AsO preferentially inhibited IFN- secretion as compared to other cytokines such as TNF-, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, AsO induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4 T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN- inhibition, and regulatory phenotype induced by AsO. Collectively, our data suggest that AsO could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.
ABSTRACT
Los monocitos/macrófagos constituyen las células diana para el virus dengue, activando linfocitos T, liberando citoquinas proinflamatorias como el Factor de Necrosis Tumoral alfa e Interferón gamma. El objetivo del estudio fue determinar TNF-α e IFN-γ en suero de pacientes dengue IgM positivo e IgM negativo, que concurrieron al Instituto de Investigaciones en Ciencias de la Salud, de febrero a abril 2007. Se realizó un estudio analítico en 163 sueros de pacientes con dengue, 143 IgM positivo y 20 IgM negativo, de ambos sexos con edad promedio de 30 y rango entre 18 a 70 años. El anticuerpo IgM para dengue y las citoquinas fueron determinados por ELISA de captura. En los 143 sueros dengue IgM positivo, el IFN-γ se detectó en 73% (104/143) con valores entre 558 y superiores a 2000 pg/ml y en el 27% (39/143) valores por debajo del punto de corte. Se encontró una diferencia estadísticamente significativa comparado con sueros dengue IgM negativo (p = < 0.005). El TNF-α se detectó en 24% (35/143) sueros IgM positivo, de los cuales 33 presentaron valores entre 45 a 176 pg/ml y 2 con valores superiores a 2000 pg/ml. No hubo significancia estadística comparando con sueros dengue IgM negativo (p = 0.26). Niveles elevados de IFN-γ y TNF-α podrían ser considerados marcadores de pronóstico para la progresión al dengue hemorrágico. Se debería tener en cuenta la potencial significancia terapéutica de estas citoquinas que podrían ayudar en las estrategias de inhibir o inducir perfiles de citoquinas adecuadas en respuesta al dengue.
Monocytes/macrophages are target cells for dengue virus, taking part in the activation of T lymphocytes, releasing proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). The objective of this study was to determine TNF-α and IFN-γ in sera of dengue patients with IgM positive and negative who attended the Instituto de Investigaciones en Ciencias de la Salud from February to April 2007. An analytical study was performed in 163 sera of dengue patients, 143 IgM positive and 20 IgM negative, men and women with an mean age of 30 years and a range from 18 to 70 years. The IgM antibody for dengue and the serum levels of cytokines were performed by capture ELISA. Serum levels of IFN-γ were detected in 73% (104/143) of the patients with dengue IgM positive, with values between 558 and higher than 2000 pg/ml, and in 27% (39/143) were below the cut-off value. A statistically significative difference was found when they were compared with dengue IgM negative sera (p=<0.005). TNF-α serum levels were detected in 24% (35/143) of the dengue IgM positive patients, 33 patients presented values between 45 and 176 pg/ml and 2 had values above 2000 pg/ml. No statistical significance was found when these values were compared with those of dengue IgM negative sera (p=0.26). IFN-γ and TNF-α high levels could be considered prognostic markers for progression to hemorrhagic dengue. The potential therapeutic significance of these cytokines should be considered as they could help in the strategies to inhibit or induce appropriate cytokine profiles in response to dengue virus.