Crosstalk between coagulation and inflammation during Dengue virus infection

Abstract

SummaryDengue fever is the most prevalent viral disease transmitted by vectors (Aedes aegypti, Aedes albopictus) in worldwide. More than 100 million cases occur annually with a mortality rate of 5% and no safe vaccine is available. The pathogenesis of Dengue, where host and viral factors participate in the establishment of Dengue haemorrhagic fever (DHF) and Dengue shock syndrome (DSS) remains unresolved. Clinical observations have revealed significant abnormalities in coagulation and inflammation systems, with increased levels of tissue factor (TF) and the chemokine IL-8, correlating with the severity of the disease and implicating damage to endothelial vascular cells (EVC). Here we present novel insights concerning the crosstalk between the regulatory signaling pathways of the coagulation-inflammation processes, during Dengue virus (DV) infection of EVC. We found that DV up-regulates Protease Activated receptor type-1 (inflammation) and TF (coagulation) receptors, via the phosphorylation of p38 and ERK1/2 MAPKs, which favor the activation of NF-κB transcription factor. This induces pro-inflammatory (IL-8) or pro-adhesive (VCAM-1) gene expression which may lead to EVC activation. The elucidation of the basic principles that signal these processes has important implications for the design of new therapeutic strategies for DHF/DSS.

Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus‐infected mice

“…Influenza A virus (IAV) infection is a common cause of respiratory tract infection worldwide resulting in considerable mortality every year, especially in the elderly . Viral infections in general are often associated with activation of the coagulation system as part of the innate immune response . In mouse models of lethal IAV subtype H1N1 infection, there is both pulmonary activation and systemic activation of coagulation .…”

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner

“…Given that IRE1 has two functions, one as an endoribonuclease involved in the IRE1-XBP1 pathway and a second function as a kinase involved in the IRE1-JNK signaling pathway (40), it is possible that signaling through this latter pathway may be important during DENV infection, with IRE1 coupling ER stress with the activation of JNK, a mitogen-activated protein kinase (MAPK). Previous reports have demonstrated the activation of two MAPKs, p38 and ERK1/2, in DENV-infected endothelial cells, leading to the up-regulation of protease-activated receptor type-1 and tissue factor receptor via phosphorylation and suggesting an involvement in DENV pathogenesis (41). Interestingly, a recent report showed a link between cholesterol and JNK signaling and demonstrated its importance for DENV replication in infected macrophages (42).…”

Role of ERK1/2 signaling in dengue virus-induced liver injury

“…Inhibition of phosphorylated ERK1/2 by FR180204 treatment decreases liver injury and improves clinical parameters in DENV-infected Balb/c mice ERK1/2 signaling has been implicated in the apoptosis and liver injury that occurs in rabbits infected with the rabbit hemorrhagic disease virus (Garcia-Lastra et al, 2009). Following DENV infection, phosphorylated p38 MAPK is induced in vitro (Ceballos-Olvera et al, 2010;Huerta-Zepeda et al, 2008;Lee et al, 2008;Nagila et al, 2013). Inhibition of phosphorylated p38 MAPK also reduces TNF-␣ production and apoptosis in DENV-infected HepG2 cells (Nagila et al, 2013).…”

“…Following DENV infection, phosphorylated p38 MAPK is induced (Ceballos-Olvera et al, 2009;Huerta-Zepeda et al, 2008;Lee et al, 2008;Nagila et al, 2013). Inhibition of p38 MAPK reduces DENV-mediated apoptosis of HepG2 cell line (Nagila et al, 2013).…”

“…However, the role of ERK1/2 during DENV infection remains unclear. Activation of ERK1/2 occurs during DENV infection of liver cells, human endothelial cells and macrophages (Ceballos-Olvera et al, 2010;Huerta-Zepeda et al, 2008;Lee et al, 2008), but is blocked in the DENV-infected human alveolar epithelial carcinoma cell line (Chang et al, 2012). To evaluate the role of ERK1/2 in the pathogenesis of DENV infection, we examined the influence of ERK1/2 activation on DENV-mediated apoptosis in vivo.…”