Predominant Infection of CD150+ Lymphocytes and Dendritic Cells during Measles Virus Infection of Macaques

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Abstract
Measles virus (MV) is hypothesized to enter the host by infecting epithelial cells of the respiratory tract, followed by viremia mediated by infected monocytes. However, neither of these cell types express signaling lymphocyte activation molecule (CD150), which has been identified as the receptor for wild-type MV. We have infected rhesus and cynomolgus macaques with a recombinant MV strain expressing enhanced green fluorescent protein (EGFP); thus bringing together the optimal animal model for measles and a virus that can be detected with unprecedented sensitivity. Blood samples and broncho-alveolar lavages were collected every 3 d, and necropsies were performed upon euthanasia 9 or 15 d after infection. EGFP production by MV-infected cells was visualized macroscopically, in both living and sacrificed animals, and microscopically by confocal microscopy and FACS analysis. At the peak of viremia, EGFP fluorescence was detected in skin, respiratory and digestive tract, but most intensely in all lymphoid tissues. B- and T-lymphocytes expressing CD150 were the major target cells for MV infection. Highest percentages (up to 30%) of infected lymphocytes were detected in lymphoid tissues, and the virus preferentially targeted cells with a memory phenotype. Unexpectedly, circulating monocytes did not sustain productive MV infection. In peripheral tissues, large numbers of MV-infected CD11c+ MHC class-II+ myeloid dendritic cells were detected in conjunction with infected T-lymphocytes, suggesting transmission of MV between these cell types. Fluorescent imaging of MV infection in non-human primates demonstrated a crucial role for lymphocytes and dendritic cells in the pathogenesis of measles and measles-associated immunosuppression. Measles remains one of the most important causes of childhood mortality in developing countries. The virus is highly infectious and is spread via the respiratory route. According to textbook descriptions, measles virus first infects respiratory epithelial cells, followed by viremia mediated by infected monocytes. However, this order of events is inconsistent with current knowledge about receptor usage by measles virus strains. In this paper we have revisited the pathogenesis of measles by infecting non-human primates with a recombinant measles virus expressing enhanced green fluorescent protein. An important advantage of this system is that infected cells become fluorescent and can be detected with high sensitivity in living animals as well as tissue samples. Strikingly, at the peak of virus replication all lymphoid tissues were strongly fluorescent, and up to 10% of T-lymphocytes and 30% of B-lymphocytes were infected. In peripheral tissues the virus predominantly infected lymphocytes and dendritic cells, although to a lesser extent respiratory epithelial cells were also infected. We hypothesize that measles virus, like human immunodeficiency virus, utilizes dendritic cells as a vehicle to establish infection of the lymphoid system and cause immunosuppression. This study reshapes our basic view of measles pathogenesis.

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