TLR signaling cascades are mainly controlled by the MyD88dependent and TRIF-dependent pathways, which both lead to activation of NF-kB and mitogen activated protein kinases (MAPKs) [17, 46] . NF-kB and MAPKs have been suggested to have critical roles in cytokine induction [47, 48] . A recent study showed that constitutive intestinal NF-kB activation does not lead to destructive inflammation unless accompanied by activation of MAPKs such as p38 and ERK [49] . Our results that DENV-2 blocked activation of NF-kB, as well as ERK1/2, support our findings of cytokine production hampered in DENV-2-infected cells. Because both NFkB and ERK1/2 were affected, DENV may suppress an upstream molecular event such as TLR gene expression, as that has been reported for DENV infection through an ADE route [37] . We also detected TLR genes expression in DENV-2 infected J774A.1 macrophages and found that polyI:Ctriggered TLR4, TLR5 and TLR13 expression was significantly downregulated by DENV-2 ( Figure S4 , panels a-c), but not for that of TRL6, TLR7, TLR8 and TLR2 ( Figure S4 , panels d-g). In contrast, DENV-2 enhanced the gene expression of TLR1 and TLR3 triggered by polyI:C stimulation ( Figure S4 , panels h-i), suggesting that DENV-2 may modulate certain TLR genes expression in macrophage. Other possibilities, such as whether DENV protease, found to block IFN-b promoter activation [13] , may target common molecules involved in type I IFN and cytokine production in TLR signaling, or whether ISG15 that is induced by DENV-2 and functions as an inhibitor of type I IFN production [50] may also contribute to immune evasion, remain to be further studied.