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Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread.

ABSTRACT: Cell-to-cell communication is essen for the development of multicellular systems and is coordinated by soluble factors, exosomes, gap junction (GJ) channels, and the recently described tunneling nanotubes (TNTs). We and others have demonstrated that TNT-like structures are mostly present during pathogenic conditions, including HIV infection. However, the nature, function, and communication properties of TNTs are still poorly understood. In this manuscript, we demonstrate that TNTs induced by HIV infection have functional GJs at the ends of their membrane extensions and that TNTs mediate long-range GJ communication during HIV infection. Blocking or reducing GJ communication during HIV infection resulted in aberrant TNT cell-to-cell contact, compromising HIV spread and replication. Thus, TNTs and associated GJs are required for the efficient cell-to-cell communication and viral spread. Our data indicate that targeting TNTs/GJs may provide new therapeutic opportunities for the treatment of HIV.

SUBMITTER: Okafo G

PROVIDER: S-EPMC5709493 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread.

Okafo George G Prevedel Lisa L Eugenin Eliseo E

Scientific reports 20171130 1

Cell-to-cell communication is essen for the development of multicellular systems and is coordinated by soluble factors, exosomes, gap junction (GJ) channels, and the recently described tunneling nanotubes (TNTs). We and others have demonstrated that TNT-like structures are mostly present during pathogenic conditions, including HIV infection. However, the nature, function, and communication properties of TNTs are still poorly understood. In this manuscript, we demonstrate that TNTs induced by HIV ...[more]

PMID: 29192225

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Project description:Various types of intercellular connections that are essential for communication between cells are often utilized by pathogens. Recently, a new type of cellular connection, consisting of long, thin, actin-rich membrane extensions named tunneling nanotubes (TNTs), has been shown to play an important role in cell-to-cell spread of HIV and influenza virus. In the present report, we show that TNTs are frequently formed by cells infected by an alphaherpesvirus, bovine herpesvirus 1 (BoHV-1). Viral proteins, such as envelope glycoprotein E (gE), capsid protein VP26, and tegument protein Us3, as well as cellular organelles (mitochondria) were detected by immunofluorescence and live-cell imaging of nanotubes formed by bovine primary fibroblasts and oropharynx cells (KOP cells). Time-lapse confocal studies of live cells infected with fluorescently labeled viruses showed that viral particles were transmitted via TNTs. This transfer also occurred in the presence of neutralizing antibodies, which prevented free entry of BoHV-1. We conclude that TNT formation contributes to successful cell-to-cell spread of BoHV-1 and demonstrate for the first time the participation of membrane nanotubes in intercellular transfer of a herpesvirus in live cells.IMPORTANCE Efficient transmission of viral particles between cells is an important factor in successful infection by herpesviruses. Herpesviruses can spread by the free-entry mode or direct cell-to-cell transfer via cell junctions and long extensions of neuronal cells. In this report, we show for the first time that an alphaherpesvirus can also spread between various types of cells using tunneling nanotubes, intercellular connections that are utilized by HIV and other viruses. Live-cell monitoring revealed that viral transmission occurs between the cells of the same type as well as between epithelial cells and fibroblasts. This newly discovered route of herpesviruses spread may contribute to efficient transmission despite the presence of host immune responses, especially after reactivation from latency that developed after primary infection. Long-range communication provided by TNTs may facilitate the spread of herpesviruses between many tissues and organs of an infected organism.

Project description:Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood-brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. Methamphetamine (meth) is an extremely addictive central nervous system stimulant. Meth reduced gap junctional (GJ) communication by inducing internalization of connexin-43 (Cx43) in astrocytes and reducing expression of Cx36 in neurons by a mechanism involving activation of dopamine receptors (see cartoon). Meth-induced changes in Cx containing channels increased extracellular levels of glutamate and resulted in higher sensitivity of neurons and astrocytes to apoptosis in response to HIV infection.

Project description:Intercellular communication is vital to the ecosystem of cancer cell organization and invasion. Identification of key cellular cargo and their varied modes of transport are important considerations in understanding the basic mechanisms of cancer cell growth. Gap junctions, exosomes, and apoptotic bodies play key roles as physical modalities in mediating intercellular transport. Tunneling nanotubes (TNTs)-narrow actin-based cytoplasmic extensions-are unique structures that facilitate direct, long distance cell-to-cell transport of cargo, including microRNAs, mitochondria, and a variety of other sub cellular components. The transport of cargo via TNTs occurs between malignant and stromal cells and can lead to changes in gene regulation that propagate the cancer phenotype. More notably, the transfer of these varied molecules almost invariably plays a critical role in the communication between cancer cells themselves in an effort to resist death by chemotherapy and promote the growth and metastases of the primary oncogenic cell. The more traditional definition of "Systems Biology" is the computational and mathematical modeling of complex biological systems. The concept, however, is now used more widely in biology for a variety of contexts, including interdisciplinary fields of study that focus on complex interactions within biological systems and how these interactions give rise to the function and behavior of such systems. In fact, it is imperative to understand and reconstruct components in their native context rather than examining them separately. The long-term objective of evaluating cancer ecosystems in their proper context is to better diagnose, classify, and more accurately predict the outcome of cancer treatment. Communication is essential for the advancement and evolution of the tumor ecosystem. This interplay results in cancer progression. As key mediators of intercellular communication within the tumor ecosystem, TNTs are the central topic of this article.

Dataset Information

Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread.

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Tunneling nanotubes (TNT) mediate long-range gap junctional communication: Implications for HIV cell to cell spread.

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