Viral dependence on cellular ion channels – an emerging anti-viral target?

Hover, Samantha; Foster, Becky; Barr, John N.; Mankouri, Jamel

doi:10.1099/jgv.0.000712

Cited by 58 publications

(80 citation statements)

References 55 publications

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“…In this study, time of addition experiments and the progression of labelled viruses showed that the effect of cholesterol depletion on BUNV was not at the initial stage of cell penetration, but occurred during the time period when the virus escapes from the endocytic pathway. Furthermore, we showed that cholesterol depletion reduced K + accumulation in the endocytic network, leading us to question whether the role of cholesterol in BUNV entry was linked to endosomal K + homeostasis, a factor we have shown to be critical for BUNV and HAZV entry (17, 36,41).…”

Section: Discussionmentioning

confidence: 99%

Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry

Charlton

Hover

Fuller

et al. 2019

Journal of Biological Chemistry

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Article:Charlton, FW, Hover, S orcid.org/0000-0001-9190-5670, Fuller, J orcid.org/0000-0001-8801-149X et al. (4 more authors) (2019) Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry. ABSTRACTThe Bunyavirales order of segmented negative-sense RNA viruses includes > 500 isolates that infect insects, animals, and plants and are often associated with severe and fatal disease in humans. To multiply their cholesterol requirement. Taken together, our findings suggest a model in which cholesterol abundance influences endosomal K + levels and consequently the efficiency of bunyavirus infection. The ability to inhibit bunyaviruses with existing cholesterol-lowering drugs may offer new options for future antiviral interventions for pathogenic bunyaviruses. Word count: 231

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Section: Discussionmentioning

confidence: 99%

Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry

Charlton

Hover

Fuller

et al. 2019

Journal of Biological Chemistry

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“…An important difference we had previously observed between TLR7 and TLR8 signaling on CD4 + T cells was an increase in intracellular Ca 2+ triggered by TLR7 stimulation that did not occur after ssRNA40 stimulation (68). As Ca 2+ signaling has been involved in the phenotype of APC and it is an important modulator of cell responses during viral infections (69,70), we decided to examine whether TLR7 stimulation induced an increase in intracellular Ca 2+ concentration in monocytes (Fig 9A). Unlike ssRNA40, IMQ stimulation induced a significant increase in intracellular Ca 2+ concentration in a dose-dependent manner (Fig 9A).…”

Section: Tlr7-dependent Ca 2+ Signaling Inhibits Type I Ifn Responsementioning

confidence: 93%

TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection

et al. 2019

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Human blood CD14+ monocytes are bone marrow–derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I–like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I interferon (IFN) and cytokine responses to infection were RNA virus specific and differentially involved TLR7 and TLR8, which sense single-stranded RNA. These TLRs activated distinct signaling cascades in monocytes, which correlated with differences in the production of cytokines involved in the polarization of CD4+ T helper cells. Furthermore, we found that TLR7 signaling specifically increased expression of the transcription factor FOSL1, which reduced IL-27 and TNFα production by monocytes. TLR7, but not TLR8, activation of monocytes also stimulated Ca2+ flux that prevented type I IFN responses. Our work demonstrates that in human monocytes, TLR7 and TLR8 triggered different signaling pathways that contribute to distinct phenotypes during RNA virus infection. In addition, we defined individual targets within these pathways that promoted specific T helper and antiviral responses.

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“…the specific routes of endosomal translocation and the host factors required during trafficking to the ER remain largely undefined. Whilst it has long been understood that the acidification of endosomes is essential for PyV entry cues, the endosomal balance of other ions and their crucial roles during the infection of a plethora of viruses is only beginning to emerge (15, 39).…”

Section: Discussionmentioning

confidence: 99%

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

Dobson

Mankouri

Whitehouse

2019

Preprint

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19Following internalisation viruses have to escape the endocytic pathway and deliver their 20 genomes to initiate replication. Members of the Polyomaviridae transit through the 21 endolysosomal network and through the endoplasmic reticulum (ER), from which heavily 22 degraded capsids escape into the cytoplasm prior to nuclear entry. Acidification of 23 endosomes and ER entry are essential in the lifecycle of polyomaviruses, however many 24 mechanistic requirements are yet to be elucidated. Alteration of endocytic pH relies upon the 25 activity of ion channels. Using two polyomaviruses with differing capsid architecture, namely 26 Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we firstly describe methods 27 to rapidly quantify infection using an IncuCyte ZOOM instrument, prior to investigating the 28 role of K + and Ca 2+ channels during early stages of infection. Broad spectrum inhibitors 29 identified that MCPyV, but not SV40, is sensitive to K + channel modulation. In contrast, both 30 viruses are restricted by the broad spectrum Ca 2+ channel inhibitor verapamil, however 31 specific targeting of transient or long lasting Ca 2+ channel subfamilies had no detrimental 32 effect. Further investigation revealed that tetrandrine blockage of two-pore channels (TPCs), 33the activity of which is essential for endolysosomal-ER fusion, ablates infectivity of both 34 MCPyV and SV40 by preventing disassembly of the capsid, which is required for the 35 exposure of minor capsid protein nuclear signals necessary for nuclear transport. This study 36 therefore identifies a novel target to restrict the entry of polyomaviruses. 37 IMPORTANCE 38Polyomaviruses establish ubiquitous, asymptomatic infection in their host. However, in the 39 immunocompromised these viruses can cause a range of potentially fatal diseases. Through 40 the use of SV40 and MCPyV, two polyomaviruses with different capsid organisation, we 41 have investigated the role of ion channels during infection. Here, we show that Ca 2+ channel 42 activity is essential for both polyomaviruses and that MCPyV is also sensitive to K + channel 43 blockage, highlighting new mechanistic requirements of ion channels during polyomavirus 44 infection. In particular, tetrandrine blockage of endolysosomal-ER fusion is highlighted as an 45 essential modulator of both SV40 and MCPyV. Given that the role of ion channels in disease 46 have been well characterised, there is a large panel of clinically available therapeutics that Polyomaviruses (PyVs) are small double stranded DNA viruses that establish persistent 51 infections in their hosts. Whilst infections are generally asymptomatic, PyVs can cause 52 severe disease in the immunosuppressed. Common examples include BKPyV-associated 53 nephropathy and haemorrhagic cystitis, and JCPyV-induced progressive multifocal 54 leukoencephalopathy (PML) (1-3).55 In ~80% of Merkel cell carcinoma (MCC) cases, Merkel cell PyV (MCPyV) infection, clonal 56 integration and UV-mediated mutation of the viral genome occur prior to tumour c...

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Viral dependence on cellular ion channels – an emerging anti-viral target?

Cited by 58 publications

References 55 publications

Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry

Cellular cholesterol abundance regulates potassium accumulation within endosomes and is an important determinant in bunyavirus entry

TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

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