Immature CD4.sup.+CD8.sup.+ Thymocytes Are Preferentially Infected by Measles Virus in Human Thymic Organ Cultures

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Date: Sept. 24, 2012
From: PLoS ONE(Vol. 7, Issue 9)
Publisher: Public Library of Science
Document Type: Report
Length: 5,728 words
Lexile Measure: 1540L

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Author(s): Yukari Okamoto 1 , Luca A. Vricella 3 , William J. Moss 1 , 2 , Diane E. Griffin 1 , *

Introduction

Measles continues to be an important cause of child morbidity and mortality worldwide and many aspects of the pathogenesis of the disease remain poorly understood [1], [2]. Immune suppression accompanies infection and most measles deaths are due to infection with other pathogens [3]. Primary and secondary lymphoid tissues are important sites for measles virus (MeV) replication and B cells, T cells and monocytes are susceptible to infection [4]. Lymphopenia is characteristic of acute measles [5] and dysfunction of infected cells may contribute to immunologic abnormalities that include depressed delayed type hypersensitivity skin test responses [6]-[8], decreased mitogen-induced lymphoproliferation [9]-[11] and increased susceptibility to other infections [12], [13] and autoimmune disease [14]. Within these mononuclear cell populations, some subsets of cells are more susceptible to infection than others and this varies with virus strain [15], [16]. Identification of the cells of the immune system that are infected by wild type and vaccine strains of MeV is important for understanding the effects of MeV infection on the immune system.

One important determinant of cell tropism is the expression of cell surface molecules important for MeV entry. Three cellular receptors for MeV are recognized: the relatively low affinity complement regulatory protein CD46 [17], [18], present on all nucleated cells [19]; the higher affinity signaling lymphocyte activation molecule (SLAM/CD150) [20]-[22], present on subsets of activated lymphocytes and antigen-presenting cells [23]-[25]; and nectin-4 present on epithelial cells [26], [27]. These receptors interact primarily with the hemagglutinin (H) attachment protein on the surface of the virus, although virion-incorporated cellular proteins may also mediate entry into epithelial cells [28]. The H proteins of wild type (WT) strains of MeV preferentially bind CD150 [29]-[31], the primary determinant of MeV tropism for immune cells. Tissue culture-adapted and vaccine strains of MeV interact efficiently with CD46, as well as CD150 [32].

Lymphoid tissues, including the thymus, are major sites of WT MeV replication during natural infection of humans and experimental infection of nonhuman primates [33]-[36]. Because the thymus is the source of naïve T cells, thymic damage may contribute to prolonged immunologic abnormalities associated with measles [37]-[39]. The best characterized target cell in the thymus is the cortical stromal epithelial cell, which plays an important role in provision of the microenvironment necessary for differentiation of thymocytes and for generation and selection of the T cell repertoire [39]-[41]. In vitro infection of thymic epithelial cells with MeV induces terminal differentiation and apoptosis associated with production of type 1 interferon (IFN) [42], [43]. SCID-hu mice with co-implants of fetal human thymus and liver experimentally infected with tissue culture-adapted WT (Chicago-1) and WT (Bilthoven), but not vaccine (Moraten), strains of MeV show infection of thymic epithelial and myelomonocytic cells and rapid depletion of CD4 + CD8+ double positive (DP) thymocytes by apoptosis [40].

Because MeV is a human virus, the systems available to study cell tropisms, strain differences...

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Gale Document Number: GALE|A498252111