Measles Virus-Induced Block of Transendothelial Migration of T Lymphocytes and Infection-Mediated Virus Spread across Endothelial Cell Barriers

Abstract

In order to analyze whether measles virus (MV) is transported via transmigrating leukocytes across endothelial barriers or whether virus spreads via infection of endothelial cells and basolateral release, we investigated the migratory behavior of infected human primary T lymphocytes across polarized cell layers of human brain microvascular endothelial cells. We found that the capacity of lymphocytes to migrate through filter pores was only slightly affected by wild-type MV infection, whereas their capacity to migrate through endothelial barriers was drastically reduced. MV infection stimulated the expression and activation of the leukocyte integrins LFA-1 and VLA-4, mediating a strong adherence to the surface of endothelial cells. Furthermore, the formation of engulfing membrane protrusions by endothelial cells, so-called transmigratory cups, was induced, but transmigration was impaired. As a consequence of this close cell-cell contact, MV infection was transmitted from lymphocytes to the endothelium. MV envelope proteins were expressed on the apical and basolateral surfaces of infected polarized endothelial cells, and virus was released from both sides. Wild-type MV infection did not induce the formation of syncytia, suggesting virus spread from cell to cell via cell processes and contacts. Our data indicate that transendothelial migration of infected T cells is strongly inhibited, whereas virus can cross endothelial barriers by productive infection of the endothelium and subsequent bipolar virus release.Leukocyte transmigration across vascular endothelium is a highly regulated process and is central to inflammation and the immune response (23,24). Underlying mechanisms such as interaction between adhesion molecules of both cell types and cytoskeletal rearrangements may be deregulated by viral infections. After transmission to the respiratory tract, measles virus (MV) is transported via dendritic cells or monocytes to draining lymph nodes, where a massive infection in CD150-positive activated dendritic cells, lymphocytes, and macrophages is initiated (10,13,22,38). The virus is then carried via infected leukocytes in the bloodstream to different organs, thereby establishing the systemic infection. To distribute infection into various organs, including the skin and the brain, MV must overcome endothelial cell barriers either within an infected leukocyte transmigrating through the barrier as a "Trojan horse" or by infection of endothelial cells and basolateral (abluminal) virus release or cell-to-cell spread. During the rash, MV-infected microvascular endothelial cells of the skin have been observed (18, 39); however, from these histological analyses it is not clear whether virus disseminates from there to underlying epithelial cell layers, leading to local cellular infiltrations, or whether the virus is first carried to epithelial cell layers via transmigrating leukocytes.MV is a highly immunosuppressive virus known to impair various functions of leukocytes, but it is not known if the infection affects transendo...

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