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Inhibition of pSTAT1 is observed in both human and NHP primary dendritic cells

Inhibition of pSTAT1 is observed in both human and NHP primary dendritic cells. dengue fever. Interestingly, there are conflicting reports as to the ability of DENV or other flaviviruses to inhibit IFN-/ signaling. Methodology/Principal Findings In order to determine the relative inhibition of IFN-/ signaling by DENVs, a method combining flow cytometry and a four-parameter logistic regression model was established. A representative isolate from DENV-1, -3 and -4 and seventeen representative isolates encompassing all DENV-2 genotypes were evaluated. All of the DENVs evaluated in this study were capable of inhibiting IFN-/ signaling. Most of the strains were able to inhibit IFN-/ to a degree similar to DENV strain 16681; however, DENV-2 sylvatic strains demonstrated an increased inhibition of phosphorylated signal transducer and activator of transcription EAI045 (pSTAT1). Surprisingly, we were unable to observe inhibition of pSTAT1 by DENV-2 sylvatic strains or the Asian strain 16681 in non-human primate (NHP) cell lines. Analysis in primary dendritic cells suggests that DENVs are capable of inhibiting IFN signaling in these cells. However, contrary to human dendritic cells, production of IFN- was detected in the supernatant of DENV-infected dendritic cells. Conclusions The ability of DENVs to inhibit IFN-/ signaling is conserved. Although some variation in the inhibition was observed, the moderate differences may be difficult to correlate with clinical outcomes. DENVs were unable to inhibit pSTAT1 in NHP cell lines, but their ability to inhibit pSTAT1 in primary dendritic cells suggests that this may be a cell specific phenomena or due to the transformed nature of the cell lines. Author Summary Dengue is a viral illness acquired through the bite of an infected mosquito. This flu-like illness, which in rare instances can be fatal, threatens more than half of the worlds population. Both and clinical studies Rabbit Polyclonal to SLC30A4 looking at how the virus operates have consistently EAI045 found that the interferon response EAI045 is modulated by the virus during infection. We looked at the ability of dengue virus (DENV) strains to inhibit phosphorylated signal transducer and activator of transcription (pSTAT1) after EAI045 IFN- stimulation and observed that contrary to earlier published reports; all DENVs are capable of inhibiting IFN-/ signaling. Strains from the DENV-2 sylvatic genotype, which mainly infect non-human primates (NHP), displayed an increased ability to inhibit pSTAT1 compared to the Asian strain 16681. To our surprise, DENVs were only capable of inhibiting pSTAT1 in human cell lines, but not in NHP cell lines. Inhibition of pSTAT1 is observed in both human and NHP primary dendritic cells. These results have important implications in the use of NHP cell lines for studies of IFN-/ inhibition by DENV and may be a relevant consideration when using NHPs for DENV pre-clinical studies. Introduction More than half of the worlds population is at risk of acquiring an acute mosquito-borne illness known as dengue [1]. Infected individuals can be asymptomatic or display a range of clinical features. Many symptomatic dengue patients experience a mild fever, however, some develop severe dengue complications resulting in plasma leakage, hemorrhage, and organ impairment [2]. Dengue virus (DENV) contains a 10.7 kb positive strand RNA genome that encodes 3 virus structural proteins (C, prM, and E) and seven nonstructural (NS) proteins (NS1, 2A, 2B, 3, 4A, 4B and 5) [3]. There are four serotypes of DENV (DENV-1, -2, -3, & -4) and each is further sub-classified into genotypes. Some studies have observed differences in virological characteristics and clinical outcomes that associate with certain genotypes [4C7]. So far, these correlates of disease severity have been most.