Date Published: August 16, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Nadine A. Dalrymple, Erich R. Mackow.
Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The endothelium is the primary fluid barrier of the vasculature and ultimately the effects of dengue virus infection that cause capillary leakage impact endothelial cell (EC) barrier functions. The ability of dengue virus to infect the endothelium provides a direct means for dengue to alter capillary permeability, permit virus replication, and induce responses that recruit immune cells to the endothelium. Recent studies focused on dengue virus infection of primary ECs have demonstrated that ECs are efficiently infected, rapidly produce viral progeny, and elicit immune enhancing cytokine responses that may contribute to pathogenesis. Furthermore, infected ECs have also been implicated in enhancing viremia and immunopathogenesis within murine dengue disease models. Thus dengue-infected ECs have the potential to directly contribute to immune enhancement, capillary permeability, viremia, and immune targeting of the endothelium. These effects implicate responses of the infected endothelium in dengue pathogenesis and rationalize therapeutic targeting of the endothelium and EC responses as a means of reducing the severity of dengue virus disease.
Dengue viruses are transmitted by mosquitoes and infect ~50 million people annually with an additional 2.5 billion people at risk living in tropical areas [1–3]. Expanding mosquito habitats are increasing the range of dengue virus outbreaks and the occurrence of severe diseases with 5–30% mortality rates: dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [1–3]. The majority of patients are asymptomatic or display mild symptoms of dengue fever (DF) which include rapid onset of fever, viremia, headache, pain, and rash . Patients with DHF and DSS display symptoms of DF in addition to increased edema, hemorrhage, thrombocytopenia, and shock [1–3]. Although patient progression to DHF and DSS is not fully understood [3, 5], antibody-dependent enhancement (ADE) of dengue infection increases the potential for DSS and DHF [3, 6, 7]. There are four dengue virus serotypes (types 1–4) and infection by one serotype predisposes individuals to more severe disease following a subsequent infection by a different dengue serotype. The circulation of serotype-specific cross-reactive antibodies or preexisting maternal antibodies may contribute to progression to DHF/DSS by facilitating viral infection of immune cells and eliciting cytokine and chemotactic immune responses. In a murine antibody dependent enhancement model of dengue disease it was observed that a dramatic increase in infected hepatic endothelial cells (ECs) coincides with the onset of severe disease  and suggests a role for the endothelium in an immune-enhanced disease process during dengue infection.
DHF and DSS are severe manifestations of dengue virus infection that result in increased vascular permeability, hemorrhage, and shock . The presence of preexisting antibodies to dengue virus predisposes patients to severe disease following infection by a second dengue serotype . A myriad of responses are associated with dengue infection that may contribute to disease, but the pathogenic mechanisms that result in DHF and DSS remain ambiguous [1–3, 26]. One common element of the dengue disease process is that enhanced immune responses increase vascular permeability by acting on the endothelium. Although it is clear that immune cells and their responses contribute to pathogenesis, the endothelium, which regulates vascular leakage, has not been considered a significant component of DHF and DSS [2, 5, 34, 35, 37].
The endothelium is not a static channel that simply separates the vasculature from surrounding tissue [33–35]. The endothelium dynamically elicits responses that may contribute to immune enhancement and vascular permeability during dengue virus infection. Several hypotheses have been offered to explain the development of severe dengue disease and immune enhanced responses clearly impact barrier functions of the endothelium, but pathogenic mechanisms that result in DHF and DSS remain vague [1–3, 26]. Leakage of the vascular endothelium is a central component of dengue virus disease and studies discussed here suggest that the dengue infected endothelium may contribute to pathogenic immune responses and immune targeting of the endothelium. However, the role of dengue virus infected ECs in pathogenesis requires definitive in vivo kinetic studies which are difficult to perform in patients. The ability of the endothelium to respond to immune cells resulting in capillary permeability further highlights the importance of dengue infected ECs in pathogenesis. The central importance of the endothelium in dengue disease suggests that stabilizing fluid barrier functions of the endothelium may be a therapeutic approach for reducing vascular leakage in DHF and DSS patients [64, 65].