DC-SIGN and CD150 Have Distinct Roles in Transmission of Measles Virus from Dendritic Cells to T-Lymphocytes

Abstract

Measles virus (MV) is among the most infectious viruses that affect humans and is transmitted via the respiratory route. In macaques, MV primarily infects lymphocytes and dendritic cells (DCs). Little is known about the initial target cell for MV infection. Since DCs bridge the peripheral mucosal tissues with lymphoid tissues, we hypothesize that DCs are the initial target cells that capture MV in the respiratory tract and transport the virus to the lymphoid tissues where MV is transmitted to lymphocytes. Recently, we have demonstrated that the C-type lectin DC-SIGN interacts with MV and enhances infection of DCs in cis. Using immunofluorescence microscopy, we demonstrate that DC-SIGN⁺ DCs are abundantly present just below the epithelia of the respiratory tract. DC-SIGN⁺ DCs efficiently present MV-derived antigens to CD4⁺ T-lymphocytes after antigen uptake via either CD150 or DC-SIGN in vitro. However, DC-SIGN⁺ DCs also mediate transmission of MV to CD4⁺ and CD8⁺ T-lymphocytes. We distinguished two different transmission routes that were either dependent or independent on direct DC infection. DC-SIGN and CD150 are both involved in direct DC infection and subsequent transmission of de novo synthesized virus. However, DC-SIGN, but not CD150, mediates trans-infection of MV to T-lymphocytes independent of DC infection. Together these data suggest a prominent role for DCs during the initiation, dissemination, and clearance of MV infection. Despite the availability of an effective vaccine, measles virus (MV) is still a major cause of childhood morbidity and mortality in developing countries. Almost all non-vaccinated children catch the highly contagious virus during an MV outbreak. This suggests an efficient route for primary infection. However, the main target cells for MV replication, CD150⁺ lymphocytes, are barely present in the respiratory tract where MV enters the body. Here we demonstrate an alternative route of MV transmission: dendritic cells that are abundantly present in the sub-epithelial tissues of the respiratory tract may capture MV through binding to either CD150 or DC-SIGN. Although some virus particles are processed for antigen presentation, others escape from degradation. After virus capture, DCs migrate to the lymphoid tissues where they encounter CD150⁺ lymphocytes and transmit the virus, after which viral replication is started. Our data provide new insights into the transmission of measles virus, and suggest a dual role for DCs in the pathogenesis of measles.