Measles Virus Infection of Alveolar Macrophages and Dendritic Cells Precedes Spread to Lymphatic Organs in Transgenic Mice Expressing Human Signaling Lymphocytic Activation Molecule (SLAM, CD150)

Abstract

Recent studies of primate models suggest that wild-type measles virus (MV) infects immune cells located in the airways before spreading systemically, but the identity of these cells is unknown. To identify cells supporting primary MV infection, we took advantage of mice expressing the MV receptor human signaling lymphocyte activation molecule (SLAM, CD150) with human-like tissue specificity. We infected these mice intranasally (IN) with a wild-type MV expressing green fluorescent protein. One, two, or three days after inoculation, nasal-associated lymphoid tissue (NALT), the lungs, several lymph nodes (LNs), the spleen, and the thymus were collected and analyzed by microscopy and flow cytometry, and virus isolation was attempted. One day after inoculation, MV replication was documented only in the airways, in about 2.5% of alveolar macrophages (AM) and 0.5% of dendritic cells (DC). These cells expressed human SLAM, and it was observed that MV infection temporarily enhanced SLAM expression. Later, MV infected other immune cell types, including B and T lymphocytes. Virus was isolated from lymphatic tissue as early as 2 days post-IN inoculation; the mediastinal lymph node was an early site of replication and supported high levels of infection. Three days after intraperitoneal inoculation, 1 to 8% of the mediastinal LN cells were infected. Thus, MV infection of alveolar macrophages and subepithelial dendritic cells in the airways precedes infection of lymphocytes in lymphatic organs of mice expressing human SLAM with human-like tissue specificity.Measles virus (MV), a member of the Morbillivirus genus of the Paramyxoviridae family, causes measles, a highly contagious disease transmitted by respiratory aerosols that induces a transient but severe immunosuppression (16,39). In spite of eradication efforts, MV still accounts for about 4% of deaths worldwide in children under 5 years of age (4, 28), due mainly to opportunistic secondary infections facilitated by MV-induced immune suppression (16). Experimental analyses of the mechanisms of pathogenesis, including the characterization of cells and tissues supporting primary MV infection, is limited by host species specificity: old world monkeys and humans are the only natural MV hosts.MV replication has been characterized mainly around the time of rash appearance, 10 to 14 days after experimental infection of monkeys (8,9,26,46). Viremia in blood cells peaks at or slightly before rash; infected B and T lymphocytes, monocytes, and dendritic cells (DC) are detected, while little if any cell-free virus is produced. Infected cells express the signaling lymphocytic activation molecule (SLAM, CD150), the lymphatic cell MV receptor (13,20,47). More information about the cellular targets of wild-type MV infection in the airways immediately after contagion is sought; recent studies of monkeys have suggested that MV may replicate initially in immune cells in the airways (8, 24) rather than in lung epithelial cells as previously postulated (5, 37).The limited availability and high ...

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

“…On the basis of the results of ex vivo DNA fragmentation assays, comparing AMs exposed to hMPV or RSV, the most likely explanation for the much more rapid disappearance of AMs from the airways of RSV-infected mice compared with hMPVinfected mice appears to be the much faster necrotic process that is triggered by RSV, similar to what has been demonstrated for influenza (48). Thus, it is possible that hMPV would establish an initial cycle of entry and replication in AMs, without killing the cells, and this initial "Trojan horse" process would be critical for subsequent progression of the infection and spreading to the airway epithelium, similar to what has been reported recently for measles virus, another member of the Paramyxoviridae family (49). Therefore, when AMs are depleted, as in our experimental mouse model, hMPV is severely impaired in its capacity to progress to a full-blown infection, resulting in lower viral replication in the lung and blunted disease.…”

Nectin-4-Dependent Measles Virus Spread to the Cynomolgus Monkey Tracheal Epithelium: Role of Infected Immune Cells Infiltrating the Lamina Propria

“…The use of airway macrophages and dendritic cells as vehicles to cross the epithelial barrier during early MV infection stages is well documented (10,29). Moreover, other systemic viruses that are transmitted by aerosol may use myeloid cells to initiate systemic spread (30,31).…”

Canine Distemper Virus Epithelial Cell Infection Is Required for Clinical Disease but Not for Immunosuppression

“…After transmission by aerosol, morbilliviruses cross the respiratory epithelium to reach immune tissues via infected immune cells, most likely macrophages or dendritic cells (6,11,13,33). Nevertheless, since it is conceivable that epithelial cell infection sustains virulence in late infection stages, we sought to confer an EpR-blind phenotype to an extremely virulent CDV strain that is lethal for ferrets.…”

“…Measles virus (MeV), which infects humans and certain nonhuman primates, is generally associated with mild to moderate clinical signs (5), while the closely related Canine distemper virus (CDV) infects a broad range of carnivores and causes severe and frequently lethal disease (2). Upon aerosol transmission, these viruses initially target signaling lymphocyte activation molecule (SLAM; CD150)-expressing immune cells in the respiratory tract (6,11), followed by dissemination throughout the lymphatic system (4,33). SLAM proteins from different host species serve as receptors for multiple morbilliviruses (31), and the amino acid residues involved in the interaction of the MeV and CDV attachment (H) proteins with SLAM are structurally conserved (32,34).…”