Early target cells of measles virus after aerosol infection of non-human primates

Ken Lemon, Rory D de Vries, Annelies W Mesman, Stephen McQuaid, Geert van Amerongen, Selma Yüksel, Martin Ludlow, Linda J Rennick, Thijs Kuiken, Bertus K Rima, Teunis B H Geijtenbeek, Albert D M E Osterhaus, W Paul Duprex, Rik L de Swart

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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 rMV(KS)EGFP 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.
Original languageEnglish
Article numbere1001263
JournalPLoS Pathogens
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 2011

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Measles virus
Aerosols
Primates
Infection
Lymphoid Tissue
Viruses
Respiratory System
Sudan
Viremia
Bronchi
Lymph Nodes
Epithelial Cells
Alveolar Epithelial Cells
Adenoids
Palatine Tonsil
Therapeutic Irrigation
Macaca
Lymphocyte Activation
Fluorescence Microscopy
Dendritic Cells

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Lemon, K., de Vries, R. D., Mesman, A. W., McQuaid, S., van Amerongen, G., Yüksel, S., ... de Swart, R. L. (2011). Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathogens, 7(1), [e1001263]. https://doi.org/10.1371/journal.ppat.1001263
Lemon, Ken ; de Vries, Rory D ; Mesman, Annelies W ; McQuaid, Stephen ; van Amerongen, Geert ; Yüksel, Selma ; Ludlow, Martin ; Rennick, Linda J ; Kuiken, Thijs ; Rima, Bertus K ; Geijtenbeek, Teunis B H ; Osterhaus, Albert D M E ; Duprex, W Paul ; de Swart, Rik L. / Early target cells of measles virus after aerosol infection of non-human primates. In: PLoS Pathogens. 2011 ; Vol. 7, No. 1.
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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 rMV(KS)EGFP 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.",
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Lemon, K, de Vries, RD, Mesman, AW, McQuaid, S, van Amerongen, G, Yüksel, S, Ludlow, M, Rennick, LJ, Kuiken, T, Rima, BK, Geijtenbeek, TBH, Osterhaus, ADME, Duprex, WP & de Swart, RL 2011, 'Early target cells of measles virus after aerosol infection of non-human primates', PLoS Pathogens, vol. 7, no. 1, e1001263. https://doi.org/10.1371/journal.ppat.1001263

Early target cells of measles virus after aerosol infection of non-human primates. / Lemon, Ken; de Vries, Rory D; Mesman, Annelies W; McQuaid, Stephen; van Amerongen, Geert; Yüksel, Selma; Ludlow, Martin; Rennick, Linda J; Kuiken, Thijs; Rima, Bertus K; Geijtenbeek, Teunis B H; Osterhaus, Albert D M E; Duprex, W Paul; de Swart, Rik L.

In: PLoS Pathogens, Vol. 7, No. 1, e1001263, 01.2011.

Research output: Contribution to journalArticle

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AU - Lemon, Ken

AU - de Vries, Rory D

AU - Mesman, Annelies W

AU - McQuaid, Stephen

AU - van Amerongen, Geert

AU - Yüksel, Selma

AU - Ludlow, Martin

AU - Rennick, Linda J

AU - Kuiken, Thijs

AU - Rima, Bertus K

AU - Geijtenbeek, Teunis B H

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AU - Duprex, W Paul

AU - de Swart, Rik L

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N2 - 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 rMV(KS)EGFP 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.

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Lemon K, de Vries RD, Mesman AW, McQuaid S, van Amerongen G, Yüksel S et al. Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathogens. 2011 Jan;7(1). e1001263. https://doi.org/10.1371/journal.ppat.1001263