Early Target Cells of Measles Virus after Aerosol Infection of Non-Human Primates

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.

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).…”

“…Experimental inoculation of rhesus and cynomolgus monkeys with recombinant MV, either expressing reporter proteins or carrying specific defects, has greatly enhanced our understanding of MV pathogenesis (8,9). After inoculation of the host with aerosolized virus, infection is detected first in resident immune cells of the lower respiratory tract (10). The virus then spreads to lymph nodes, where it infects a broad range of immune cells expressing the signaling lymphocytic activation molecule (CD150/SLAM) (8,11,12).…”

“…However, since the tracheal localization of EpR/nectin-4 was not known, questions regarding the spread of infection in the tracheal epithelium were not addressed. Moreover, comparison of virusshedding efficiencies was based on a historic control group rather than a simultaneously infected group (10,21).…”

Nipah Virus Entry and Egress from Polarized Epithelial Cells

“…Since epithelial tissues act as barriers between body cavities and underlying tissues, viruses have to adapt to find ways across. To penetrate the epithelial barrier, viruses such as HIV, Epstein-Barr virus, hepatitis C virus, or measles virus use cells of the immune system with innate capacities to cross epithelia (macrophages and dendritic cells) as "Trojan horses" (53)(54)(55)(56). Adenoviruses exploit cytokine secretion activities of macrophages associated with the apical surface of the epithelium to induce a redistribution of their basolateral receptors to the apical surface, where they mediate virus entry (57).…”

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

“…CD150 is the primary receptor for wild-type MV [20], whereas the laboratory-adapted MV strain Edmonston also uses CD46 as entry receptor [21]. Wild-type MV initially replicates in mononuclear cells in the alveolar lumen, the bronchus-associated lymphoid tissue and the regional lymph nodes of the respiratory tract, followed by viremia and systemic disease [19,22]. Although measles is associated with immune suppression, MV paradoxically induces a strong cellular and humoral immune response that efficiently clears the virus and results in lifelong immunity [23].…”