Human Cytomegalovirus (HCMV) Infection of Endothelial Cells Promotes Naïve Monocyte Extravasation and Transfer of Productive Virus To Enhance Hematogenous Dissemination of HCMV

Abstract

Human cytomegalovirus (HCMV) pathogenesis is dependent on the hematogenous spread of the virus to host tissue. While data suggest that infected monocytes are required for viral dissemination from the blood to the host organs, infected endothelial cells are also thought to contribute to this key step in viral pathogenesis. We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions. Together, our results provide evidence for an active role of the infected endothelium in HCMV dissemination and pathogenesis.Human cytomegalovirus (HCMV) is a betaherpesvirus that establishes a life-long persistent infection (10). In immunocompromised individuals, such as AIDS patients, neonates, and transplant recipients, HCMV infection is associated with significant morbidity and mortality (13,38,56,87). In immunocompetent hosts, HCMV infection is generally asymptomatic, although it can cause mononucleosis (40) and is associated with chronic inflammatory diseases, such as the cardiovascular diseases atherosclerosis and coronary restenosis (1,19,35,46,51,57,59,86,90,107).HCMV pathogenesis is a direct result of viral spread to host organs and the subsequent infection of those organ systems (6,44,54,83). Systemic spread occurs during both asymptomatic and symptomatic infections (93) and is required for HCMV persistence in the host (83). During primary infection, the virus spreads from the initial site of infection to the peripheral blood and then to host organ tissue (6,54,83). In healthy hosts, infection of these organ systems allows for the establishment of the viral persistence needed for viral survival in the infected host and in the general population. In contrast, in immunocompromised hosts, because of the absence of a functional immune response, this same strategy of viral spread would lead to the overt organ disease seen in these individuals (83).The mechanisms of HCMV dissemination remain unclear; however, cells of the ...

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