Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Panasiuk, Mirosława; Rychłowski, Michał; Derewońko, Natalia; Bieńkowska-Szewczyk, Krystyna

doi:10.1128/jvi.00090-18

Cited by 89 publications

(83 citation statements)

References 56 publications

(61 reference statements)

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“…5. Alternatively, some studies have suggested that subviral components may be transferred directly to adjacent cells through transient pores or other intercellular connection mechanisms, such as tunneling nanaotubes (45, 76, 77). Overall, specific infectivity of virions might have a dramatic effect on the efficiency of the cell-free route (2a-4a) where the virus is subject to physical limitations related to diffusion and to inactivation by neutralizing antibodies, complement components, and other host defenses.…”

Section: Discussionmentioning

confidence: 99%

Specialization for cell-free or cell-to-cell spread of BAC-cloned HCMV strains is determined by factors beyond the UL128-131 and RL13 loci

Schultz

Lanchy

Day

et al. 2019

Preprint

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ABSTRACTIt is widely held that clinical isolates of human cytomegalovirus (HCMV) are highly cell-associated, and mutations affecting the UL128-131 and RL13 loci that arise in culture lead to the appearance of a cell-free spread phenotype. The BAC-clone Merlin (ME), expresses abundant UL128-131, is RL13-impaired and produces low infectivity virions in fibroblasts, whereas TB40/e (TB) and TR are low in UL128-131, RL13-intact and produce virions of much higher infectivity. Despite these differences, quantification of spread by flow cytometry revealed remarkably similar spread efficiencies in fibroblasts. In epithelial cells, ME spread more efficiently, consistent with robust UL128-131 expression. Strikingly, ME spread far better than TB or TR in the presence of neutralizing antibodies on both cell types, indicating that ME is not simply deficient at cell-free spread, but is particularly efficient at cell-to-cell spread, whereas TB and TR cell-to-cell spread is poor. Sonically disrupted ME-infected cells contained scant infectivity, suggesting that the efficient cell-to-cell spread mechanism of ME depends on features of the intact cells such as junctions or intracellular trafficking processes. Even when UL128-131 was transcriptional repressed, cell-to-cell spread of ME was still more efficient than TB or TR. Moreover, RL13 expression comparably reduced both cell-free and cell-to-cell spread of all three strains, suggesting that it acts at a stage of assembly and/or egress common to both routes of spread. Thus, HCMV strains can be highly specialized for either for cell-free or cell-to-cell spread and these phenotypes are determined by factors beyond the UL128-131 or RL13 loci.IMPORTANCEBoth cell-free and cell-to-cell spread are likely important for the natural biology of HCMV. In culture, strains clearly differ in their capacity for cell-free spread as a result of differences in the quantity and infectivity of extracellular released progeny. However, it has been unclear whether “cell-associated” phenotypes are simply the result of poor cell-free spread, or are indicative of particularly efficient cell-to-cell spread mechanisms. By measuring the kinetics of spread at early time points, we were able to show that HCMV strains can be highly specialized to either cell-free or cell-to-cell mechanisms, and this was not strictly linked the efficiency of cell-free spread. Our results provide a conceptual approach to evaluating intervention strategies for their ability to limit cell-free or cell-to-cell spread as independent processes.

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Section: Discussionmentioning

confidence: 99%

Specialization for cell-free or cell-to-cell spread of BAC-cloned HCMV strains is determined by factors beyond the UL128-131 and RL13 loci

Schultz

Lanchy

Day

et al. 2019

Preprint

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“…On the other hand, oAβ is implicated in PAK1 dependent synaptic dysfunctions and PAK1 is aberrantly activated and translocated from the cytosol to the membrane during the development of pathology in the AD brain . Interestingly, HIV and HSV viruses exploit PAK1 kinase dependent macropinocytosis en route and recent studies have also shown direct cell-to-cell spreading of HIV and HSV virus via TNTs Panasiuk et al, 2018). Interesting another report has shown that HIV-1 Nef protein mediated TNT formation associated with 5 proteins of exocyst complex and they involve in a PAK2 and Rab 11 dependent pathway (Mukerji et al, 2012).…”

Section: Oaβ Propagation To Healthy Cells Is Mediated By Transport Inmentioning

confidence: 99%

Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

Öllinger

Kågedal

Nath

2019

Preprint

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The progressive pathology development in Alzheimer's disease is due to direct 12 transfer of amyloid-β1-42 oligomers (oAβ) between connected neurons. However, the 13 mechanism of transfer is not revealed yet. Here we show that internalization of toxic oAβ in 14 SH-SY5Y cells, causes cellular stress detected as significant membrane surface expansion. 15 Subsequently, protrusions appear in the form of tunnelling nanotubes (TNTs). The TNTs 16 propagate oAβ and organelles directly from one cell-to-another. Preceding the formation, we 17 detect oAβ induced plasma membrane damage and repair through lysosomal-exocytosis 18 followed by endocytosis to re-establish the membrane. Eventually, the non-degradable 19 internalized oligomers accumulate in lysosomes. Direct transfer of neurodegenerative proteins 20 via TNTs has recently been suggested as means of pathology spreading. However, molecular 21 basis of TNTs formation is unexplored. The present study is giving the insight that sprouting 22 of TNTs might instigate as consequences of oAβ induced membrane damage and perturbed 23 membrane repair process in the stressed cells, probably to maintain cell surface expansion 24 and/or membrane-tension in equilibrium. 25 26 Summary: TNTs were recently discovered as novel route in cell-to-cell pathology spreading 27 of many diseases. Here we show that TNTs instigate as a consequences of perturbed membrane 28 repair process in oAβ accumulated stressed cells. The mechanistic understanding has enormous 29 pathophysiology significance.30 31 Short title: Direct cell-to-cell transfer of Aβ oligomers in TNTs. 32 33 2

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“…TNTs are defined as thin (50‐200 nm), fragile, and dynamic structures, consisting of plasma membrane and filamentous (F)‐actin . They are involved in cell‐to‐cell interaction and intercellular transport of organelles and pathogens such as virus and bacteria . Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro .…”

Section: Introductionmentioning

confidence: 99%

“…16,17 They are involved in cell-to-cell interaction and intercellular transport of organelles and pathogens such as virus and bacteria. 16,[18][19][20][21][22][23][24] Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro. [25][26][27][28][29][30][31][32] TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug-efflux in aggressive forms of pancreatic carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

et al. 2020

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Chronic myeloid leukemia (CML) is a stem cell disease of the bone marrow where mechanisms of inter‐leukemic communication and cell‐to‐cell interactions are proposed to be important for optimal therapy response. Tunneling nanotubes (TNTs) are novel intercellular communication structures transporting different cargos with potential implications in therapy resistance. Here, we have investigated TNTs in CML cells and following treatment with the highly effective CML therapeutics tyrosine kinase inhibitors (TKIs) and interferon‐α (IFNα). CML cells from chronic phase CML patients as well as the blast crisis phase cell lines, Kcl‐22 and K562, formed few or no TNTs. Treatment with imatinib increased TNT formation in both Kcl‐22 and K562 cells, while nilotinib or IFNα increased TNTs in Kcl‐22 cells only where the TNT increase was associated with adherence to fibronectin‐coated surfaces, altered morphology, and reduced movement involving β1integrin. Ex vivo treated cells from chronic phase CML patients showed limited changes in TNT formation similarly to bone marrow cells from healthy individuals. Interestingly, in vivo nilotinib treatment in a Kcl‐22 subcutaneous mouse model resulted in morphological changes and TNT‐like structures in the tumor‐derived Kcl‐22 cells. Our results demonstrate that CML cells express low levels of TNTs, but CML therapeutics increase TNT formation in designated cell models indicating TNT functionality in bone marrow derived malignancies and their microenvironment.

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Tunneling Nanotubes as a Novel Route of Cell-to-Cell Spread of Herpesviruses

Cited by 89 publications

References 56 publications

Specialization for cell-free or cell-to-cell spread of BAC-cloned HCMV strains is determined by factors beyond the UL128-131 and RL13 loci

Specialization for cell-free or cell-to-cell spread of BAC-cloned HCMV strains is determined by factors beyond the UL128-131 and RL13 loci

Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting p21-activated kinase dependent actin remodulation

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

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