Tunneling nanotubes (TNTs) are actin-based intercellular conduits that connect distant cells and allow intercellular transfer of molecular information, including genetic information, proteins, lipids, and even organelles. Besides providing a means of intercellular communication, TNTs may also be hijacked by pathogens, particularly viruses, to facilitate their spread. Viruses of many different families, including retroviruses, herpesviruses, orthomyxoviruses, and several others have been reported to trigger the formation of TNTs or TNT-like structures in infected cells and use these structures to efficiently spread to uninfected cells. In the current review, we give an overview of the information that is currently available on viruses and TNT-like structures, and we discuss some of the standing questions in this field.
Tunneling nanotubes (TNTs) are long bridge-like structures that connect eukaryotic cells and mediate intercellular communication. We found earlier that the conserved alphaherpesvirus US3 protein kinase induces long cell projections that contact distant cells and promote intercellular virus spread. In this report, we show that the US3-induced cell projections constitute TNTs. In addition, we report that US3-induced TNTs mediate intercellular transport of information (i.e. GFP) in the absence of other viral proteins. US3-induced TNTs are remarkably stable compared to most TNTs described in literature. In line with this, US3-induced TNTs were found to contain stabilized (acetylated and detyrosinated) microtubules. Transmission electron microscopy showed that virus particles are individually transported in membrane-bound vesicles in US3-induced TNTs and are released along the TNT and at the contact area between TNT and adjacent cell. Contact between US3-induced TNTs and acceptor cells is very stable, which correlated with a marked enrichment in adherens junction components beta-catenin and E-cadherin at the contact area. These data provide new structural insights in US3-induced TNTs and how they may contribute to intercellular communication and alphaherpesvirus spread. Tunneling nanotubes (TNT) represent an important, yet still poorly understood mode of long distance intercellular communication. We and others reported earlier that the conserved alphaherpesvirus US3 protein kinase induces long cellular protrusions in infected and transfected cells. Here, we show that US3-induced cell projections constitute TNTs, based on structural properties and transport of biomolecules. In addition, we report on different particular characteristics of US3-induced TNTs that aid to explain their remarkable stability compared to physiological TNTs. In addition, transmission electron microscopy assays indicate that, in infected cells, virions travel in the US3-induced TNTs in membranous transport vesicles, and leave the TNT via exocytosis. These data generate new fundamental insights in the biology of (US3-induced) TNTs, and how they may contribute to intercellular virus spread and communication.
Small intestinal organoids, or enteroids, represent a valuable model to study host–pathogen interactions at the intestinal epithelial surface. Much research has been done on murine and human enteroids, however only a handful studies evaluated the development of enteroids in other species. Porcine enteroid cultures have been described, but little is known about their functional responses to specific pathogens or their associated virulence factors. Here, we report that porcine enteroids respond in a similar manner as in vivo gut tissues to enterotoxins derived from enterotoxigenic Escherichia coli, an enteric pathogen causing postweaning diarrhoea in piglets. Upon enterotoxin stimulation, these enteroids not only display a dysregulated electrolyte and water balance as shown by their swelling, but also secrete inflammation markers. Porcine enteroids grown as a 2D-monolayer supported the adhesion of an F4+ ETEC strain. Hence, these enteroids closely mimic in vivo intestinal epithelial responses to gut pathogens and are a promising model to study host–pathogen interactions in the pig gut. Insights obtained with this model might accelerate the design of veterinary therapeutics aimed at improving gut health.
Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections.
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