Abstract
Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. Hantavirus-infected endothelial cells (EC) display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE)-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF). To examine endothelial leakage in a relevant in vitro system, we co-cultured endothelial and vascular smooth muscle cells (vSMC) to generate capillary blood vessel-like structures. In contrast to results obtained in monolayers of cultured EC, we found that despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation. Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS). We show that incubation of factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK). Measuring cell permeability in real-time using electric cell-substrate impedance sensing (ECIS), we identified dramatic increases in endothelial cell permeability after KKS activation and liberation of BK. Furthermore, the alterations in permeability could be prevented using inhibitors that directly block BK binding, the activity of FXIIa, or the activity of KAL. Lastly, FXII binding and autoactivation is increased on the surface of hantavirus-infected EC. These data are the first to demonstrate KKS activation during hantavirus infection and could have profound implications for treatment of hantavirus infections.
Highlights
The Bunyaviridae family encompasses viruses that cause numerous hemorrhagic fever diseases in humans
A perplexing finding is that the vascular endothelium remains intact during hantavirus infection and with no apparent cytopathic effects to explain leakage and edema
Our studies show for the first time that hantavirusinfected endothelial cells (EC) have increased kallikrein-kinin system (KKS) activation resulting in liberation of the inflammatory peptide, BK
Summary
The Bunyaviridae family encompasses viruses that cause numerous hemorrhagic fever diseases in humans. The genus Hantavirus includes Old World and New World viral lineages. Old World hantaviruses are widespread throughout Asia and Europe and are associated with the clinical syndrome, hemorrhagic fever with renal syndrome (HFRS). The prototype hantavirus, Hantaan virus (HTNV), can cause severe HFRS with a case fatality rate as high as 15% [1,2]. The New World hantaviruses are the causative agents of hantavirus pulmonary syndrome (HPS) and are found in the Americas [1,2]. The case fatality rate for HPS is greater than that of HFRS and has been reported to be as high as 50% for Andes virus (ANDV) [1]
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