Upregulation of the Suppressors of Cytokine Signaling 1 and 3 Is Associated with Arrest of Phosphorylated-STAT1 Nuclear Importation and Reduced Innate Response in Denguevirus-Infected Macrophages

Abstract

To clarify whether the suppressors of cytokine signaling (SOCS) are associated with denguevirus (DENV) evasion of the antiviral response, we analyzed the expression kinetics of SOCS1 and SOCS3 and of the antiviral genes MxA and OAS during DENV infection of U937 macrophages that were or not treated with interferon (IFN)-α. DENV infection produced a viral titer three times higher in untreated than in IFN-α-treated cells (p < 0.001 at 72 h postinfection [p.i.]). Partial inhibition of DENV replication was associated with reduced expression of MxA and OAS antiviral genes as well as higher SOCS1 and SOCS3 expression in DENV-infected cells than in cells treated only with IFN-α. Complete loss of phosphorylated-signal transducer and activator of transcription (p-STAT)2 and reduced nuclear importation of p-STAT1 were observed in DENV-infected cells compared to IFN-α treatment that induced p-STAT1 and p-STAT2. Our data thus suggest that overexpression of SOCS1 and SOCS3 induced by DENV infection leads to impairment of antiviral response through the inhibition of STAT functionality.

IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever

“…In agreement, simultaneous increase of IL-6 and IL-10 in DHF is indicative of the dysregulated immune response that leads to the progress of dengue severity [ 49 ]. The changes in cytokine expression found in this study suggest that deregulation of socs1 and socs3 expression induced by dengue virus infection [ 28 , 29 ] is not just involved in cytokine imbalance but also promotes the persistent inflammatory response that contributes to increased vascular permeability and hemorrhagic manifestations. However, further mechanistic studies are required to clarify how these regulatory factors are altered during dengue infection.…”

“…socs1 is another negative regulator of cytokine signaling affected by dengue infection [ 28 , 29 ]. Chen et al reported a decrease in socs1 expression in DHF with respect to DF patients, which was associated with low levels of IFN- γ and high levels of IL-10 during defervescence [ 27 ], similar to our results.…”

“…socs3 is expressed by a feedback signal in response to IL-6, which led to a downregulation of IL-6 response and synthesis [ 44 ]. We have previously found that socs3 overexpression in dengue-infected cells contributes to evasion of the innate immune response [ 28 , 29 ]. In agreement, simultaneous increase of IL-6 and IL-10 in DHF is indicative of the dysregulated immune response that leads to the progress of dengue severity [ 49 ].…”

“…We have previously found that DENV infection induced high expression of socs1 and socs3 in macrophages derived from the U-937 cell line, being socs1 ten times more expressed than socs3 . Those changes were associated with evasion of the antiviral innate immune response in dengue-infected cells [ 28 , 29 ]. Here, we studied the immune response of patients during the first dengue outbreak identified in Puebla state, in a geographical area that delimits three dengue endemic states, but that differs in height above sea level and climate.…”

Taraxacum officinale and Urtica dioica extracts inhibit dengue virus serotype 2 replication in vitro

“…Subsequently the viral supernatant was centrifuged for 5 min at 10,000 rpm to remove the cell debris. Aliquots were stored at − 70 °C until use [ 32 , 33 ].…”