Abstract
Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMVKSEGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n = 3 per time point) and infected (EGFP+) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP+ cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia.
Highlights
Measles virus (MV) is one of the most contagious human viruses known, and is transmitted via aerosols or by direct contact with contaminated respiratory secretions
Epithelial cells in the upper respiratory tract have long been considered as early target cells, but more recently alveolar macrophages (AM) and dendritic cells (DC) have been proposed as alternatives
These infected cells migrated through the bronchus-associated lymphoid tissue to the draining tracheo-bronchial lymph node at 3 days post-infection
Summary
Measles virus (MV) is one of the most contagious human viruses known, and is transmitted via aerosols or by direct contact with contaminated respiratory secretions. In 1993 the membrane cofactor protein CD46, expressed by virtually all nucleated human cells, was the first protein to be identified as MV receptor [4,5]. Signaling lymphocyte activation molecule (SLAM or CD150), a membrane glycoprotein expressed on subsets of immune cells, was identified as the receptor for wild-type MV strains in 2000 [7,8]. It is generally accepted that pathogenic wild-type MV strains use CD150 as high affinity cellular receptor, whereas vaccine and laboratory-adapted strains can use either CD46 or CD150. Distribution of CD150 explains most, but not all aspects of measles pathogenesis and it may be possible that the utilization of additional low-affinity cellular receptors explains how wild-type viruses enter CD1502 epithelial or neuronal cells [9,10,11]
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