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
]. 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
]. 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 [4
]. Patients with DHF and DSS display symptoms of DF in addition to increased edema, hemorrhage, thrombocytopenia, and shock [1
]. Although patient progression to DHF and DSS is not fully understood [3
], antibody-dependent enhancement (ADE) of dengue infection increases the potential for DSS and DHF [3
]. 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 [8
] and suggests a role for the endothelium in an immune-enhanced disease process during dengue infection.
The major target tissues for dengue virus infection have been difficult to determine but virus has been isolated from human blood, lymph node, bone marrow, liver, heart, and spleen [9
]. Blood samples are more easily obtained from dengue patients than tissues and yield a wide array of information about cytokine responses elicited by dengue virus infection [1
]. While many of these cytokines are present in DF patients, the majority of them are increased during DHF. Overall, DHF responses include greater cytokine production, T- and B-cell activation, complement activation, and T-cell apoptosis [3
]. Complement pathway activation and elevated levels of complement proteins C3, C3a, and C5a are significant in that they can direct opsonization, chemotaxis of mast and other immune cells, and direct the localized release of the vascular permeability factor histamine from mast cells [17
]. Importantly, cytokines and complement factor responses all act on the endothelium and alter normal fluid barrier functions of ECs.
The ability of dengue virus to infect immune, dendritic, and endothelial cells fosters a role for immune responses to act on the endothelium and increase capillary permeability [5
]. However, the redundant nature of capillary barrier functions suggests that permeability is likely to be multifactorial in nature with many factors working in concert to modulate EC responses and permeabilize the endothelium. Dengue infected ECs are observed in DHF/DSS patient autopsy samples and in murine dengue virus disease models [8
]. This suggests that dengue infected ECs may also contribute directly to pathogenesis by increasing viremia, secreting cytokines, modulating complement pathways, or transforming the endothelium into an immunologic target of cellular and humoral immune responses.
Plasma constituents contain factors secreted by an estimated ~1013
ECs present in the body, and autopsy samples and murine dengue disease models clearly demonstrate that vascular ECs are infected [8
]. The endothelium is the primary fluid barrier of the vasculature and dengue virus-induced responses resulting in edema or hemorrhagic disease ultimately cause changes in EC permeability. Unique EC receptors, adherens junctions, and signaling pathways respond to cytokines, permeability factors, immune complexes, clotting factors, and platelets, normally acting in concert to control vascular leakage [5
]. Virally induced changes in endothelial or immune cell responses have the potential to alter this orchestrated balance with pathologic consequences [5
]. However, very little is known about the role of dengue virus-infected ECs in disease or the kinetics, timing, and replication of dengue viruses within patient ECs. The inability to kinetically study the endothelium in dengue patients and the relative ease of assessing blood components has resulted in a focus on immune cells instead of ECs. Yet, the endothelium is the ultimate target of permeabilizing responses. Here, we discuss studies of dengue infected ECs and the potential for the dengue infected endothelium to contribute to dengue pathogenesis.