Abstract
The network of tunneling nanotubes (TNTs) represents the filamentous (F)-actin rich tubular structure which is connected to the cytoplasm of the adjacent and or distant cells to mediate efficient cell-to-cell communication. They are long cytoplasmic bridges with an extraordinary ability to perform diverse array of function ranging from maintaining cellular physiology and cell survival to promoting immune surveillance. Ironically, TNTs are now widely documented to promote the spread of various pathogens including viruses either during early or late phase of their lifecycle. In addition, TNTs have also been associated with multiple pathologies in a complex multicellular environment. While the recent work from multiple laboratories has elucidated the role of TNTs in cellular communication and maintenance of homeostasis, this review focuses on their exploitation by the diverse group of viruses such as retroviruses, herpesviruses, influenza A, human metapneumovirus and SARS CoV-2 to promote viral entry, virus trafficking and cell-to-cell spread. The later process may aggravate disease severity and the associated complications due to widespread dissemination of the viruses to multiple organ system as observed in current coronavirus disease 2019 (COVID-19) patients. In addition, the TNT-mediated intracellular spread can be protective to the viruses from the circulating immune surveillance and possible neutralization activity present in the extracellular matrix. This review further highlights the relevance of TNTs in ocular and cardiac tissues including neurodegenerative diseases, chemotherapeutic resistance, and cancer pathogenesis. Taken together, we suggest that effective therapies should consider precise targeting of TNTs in several diseases including virus infections.
Highlights
The ability of a cell to communicate with the distant neighboring cell is vital for its survival and efficient function
Though cardiac tissue itself has limited regenerative capacity, studies have demonstrated that mesenchymal stem cells (MSCs) potentiate cardiomyocyte regeneration through cell-to-cell communication that includes paracrine signaling pathways and nanotubular connections [47]
Many medically important viruses, such as the influenza virus, human immunodeficiency virus (HIV) and herpes simplex virus, can evade host immunity and avoid pharmaceutical targeting by using tunneling nanotubes (TNTs) to pass their genomes to naive cells [12, 52]
Summary
The ability of a cell to communicate with the distant neighboring cell is vital for its survival and efficient function. TNTs exist as a cytoplasmic bridge between the two closely or distant cells They form gap-like junctions between connected cells and mediate the exchange of cytoplasmic proteins, cellular organelles (such as endoplasmic reticulum, Golgi, endosome, lysosome, mitochondria), lipids, nucleic acids, microRNA, ions, calcium, and several other components [4, 8,9,10]. Thicker TNTs contain microtubules and exceed a 7 μm diameter which allows them to transfer organelles such as mitochondria between cells [6, 12]. They facilitate both short and long-distance direct communication, spanning distances of up to 300 μm [13]. The concomitant evolution of pathogens with the cell’s ability to produce TNTs is interesting from a cellular biology standpoint and highlights the importance of targeting this mechanism of propagation to treat certain diseases
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