Manipulation of cell surface macromolecules by flaviviruses

Abstract

Cell surface macromolecules play a crucial role in the biology and pathobiology of flaviviruses, both as receptors for virus entry and as signaling molecules for cell-cell interactions in the processes of vascular permeability and inflammation. This review examines the cell tropism and pathogenesis of flaviviruses from the standpoint of cell surface molecules, which have been implicated as receptors in both virus-cell as well as cell-cell interactions. The emerging picture is one that encompasses extensive regulation and interplay among the invading virus, viral immune complexes, Fc receptors, major histocompatibility complex antigens, and adhesion molecules.

Fig 1

Model showing surface interactions of hemorrhagic flavivirus (dengue) with extra- and intravascular cell targets. Intravascularly, the presence of subneutralizing levels of antivirus antibodies stimulates virus attachment to platelets and infection of monocytes. This results in immune complex deposition on platelets and secretion of vasoactive factors from virus-infected monocytes. Among such vasoactive factors are cytokines, particularly TNF-α, which activates increased surface expression of adhesion molecules on endothelial cells. Extravascularly, virus infection of tissue macrophages, mast cells, and dendritic cells may result in the release of additional factors, which contribute to endothelial cell perturbation.

Fig 2

Model depicting possible events in endothelial cell surface perturbation during hemorrhagic flavivirus (dengue) infection. Endothelial cell activation, leading to upregulation of adhesion molecules (E-selectin, VCAM-1, ICAM-1), can be triggered by monocyte-derived cytokines (Anderson et al., 1997) or by deposition of C5b-9 and other products of complement activation (Avirutnan et al., 1998). C5b-9 is represented as a membrane attack complex pore structure, although the deposition of C5b-9 on dengue-infected cells appears associated with sublytic, rather than lytic, responses (Avirutnan et al., 1998). Increased adhesion molecule expression, along with uncharacterized vasoactive factors, can lead to endothelial leakage and can mediate rolling, adhesion, and transendothelial migration of leukocytes into extravascular tissues. Similar processes may also contribute to the invasion of cell-borne neurotropic flaviviruses through the endothelial blood–brain barrier.