Abstract
Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue.
Highlights
Introduction censeeMDPI, Basel, Switzerland.Deregulation of coagulation and fibrinolysis along with an exacerbated inflammatory response are pathological manifestations that are commonly associated to severe viral infections, such as caused by respiratory viruses (Parainfluenza, SARS-CoV, SARS-CoV-2), hemorrhagic-fever viruses (Hantavirus) and Arboviruses [1,2,3,4,5,6]
Using a well-established in vitro model of blood brain barrier [57,58], which was previously demonstrated to be productively infected by dengue virus (DENV) serotype 2 (16,681 strain) [59], we first asked whether exogenous kinins added to cultures of human microvascular endothelial cells (HBMECs) could influence the infection outcome
We asked whether mRNA levels of B2R and B1R were modulated in human brain microvascular endothelial cells (HBMECs) exposed to infective DENV or UV-inactivated virus
Summary
Deregulation of coagulation and fibrinolysis along with an exacerbated inflammatory response are pathological manifestations that are commonly associated to severe viral infections, such as caused by respiratory viruses (Parainfluenza, SARS-CoV, SARS-CoV-2), hemorrhagic-fever viruses (Hantavirus) and Arboviruses [1,2,3,4,5,6]. Pharmaceuticals 2021, 14, 56 hypotension and hypovolemic shock [5,7,8,9].
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