A central paradigm within virology is that each viral particle largely behaves as an independent infectious unit. Here, we demonstrate that clusters of enteroviral particles are packaged within phosphatidylserine (PS) lipid-enriched vesicles that are non-lytically released from cells and provide greater infection efficiency than free single viral particles. We show that vesicular PS lipids are co-factors to the relevant enterovirus receptors in mediating subsequent infectivity and transmission, in particular to primary human macrophages. We demonstrate that clustered packaging of viral particles within vesicles enables multiple viral RNA genomes to be collectively transferred into single cells. This study reveals a novel mode of viral transmission, where enteroviral genomes are transmitted from cell-to-cell en bloc in membrane-bound PS vesicles instead of as single independent genomes. This has implications for facilitating genetic cooperativity among viral quasispecies as well as enhancing viral replication.
The development of ectodermal organs, such as teeth, requires epithelial-mesenchymal interactions. Basic helixloop-helix (bHLH) transcription factors regulate various aspects of tissue development, and we have previously identified a bHLH transcription factor, AmeloD, from a tooth germ cDNA library. Here, we provide both in vitro and in vivo evidence that AmeloD is important in tooth development. We created AmeloD-knockout (KO) mice to identify the in vivo functions of AmeloD that are critical for tooth morphogenesis. We found that AmeloD-KO mice developed enamel hypoplasia and small teeth because of increased expression of E-cadherin in inner enamel epithelial (IEE) cells, and it may cause inhibition of the cell migration. We used the CLDE dental epithelial cell line to conduct further mechanistic analyses to determine whether AmeloD overexpression in CLDE cells suppresses E-cadherin expression and promotes cell migration. Knockout of epiprofin (Epfn), another transcription factor required for tooth morphogenesis and development, and analysis of AmeloD expression and deletion revealed that AmeloD also contributed to multiple tooth formation in Epfn-KO mice by promoting the invasion of dental epithelial cells into the mesenchymal region. Thus, AmeloD appears to play an important role in tooth morphogenesis by modulating E-cadherin and dental epithelial-mesenchymal interactions. These findings provide detailed insights into the mechanism of ectodermal organ development. Ectodermal organs, such as teeth, all display a need for epithelial-mesenchymal interactions for their development. Tooth development is, in fact, a good model for understanding the mechanism of ectodermal development because it has welldefined stages and distinctive differentiated cell types (1). In the mouse, the morphogenesis of the molars is divided into four stages: the initiation stage (embryonic day 11.5 (E11.5)), 2 bud stage (E13.5), cap stage (E15.5), and bell stage (E17.5). At the initiation stage, the dental epithelium starts to thicken and invades into the mesenchymal region. This invagination process forms the tooth bud, and the dental epithelium condenses at the bud stage. After the cap stage, the dental epithelial stem cells differentiate into various cell types to form the enamel organ: the inner enamel epithelium (IEE), outer enamel epithelium, stratum intermedium (SI), and stellate reticulum. The IEE cells are ameloblast progenitor cells, a unique cell population in the proliferation stage as they express proliferation markers but do not express E-cadherin, a negative regulator of cell division and migration (2, 3). The IEE cells actively proliferate and migrate to form a correctly sized enamel organ. After proliferation, the IEE cells differentiate into enamel-secreting ameloblasts. Proliferative IEE cells persist near the apical tip of the
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