Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Hacke, Moritz; Björkholm, Patrik; Hellwig, Andrea; Himmels, Patricia; Almodóvar, Carmen Ruiz de; Brügger, Britta; Wieland, Felix; Ernst, Andreas

doi:10.1038/ncomms8688

Cited by 43 publications

(39 citation statements)

References 67 publications

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“…For example, heme-oxygenase-1 (HO-1) has been shown to suppress Ebola virus replication (134), and statins are known to up regulate HO-1 (135). Moreover, Ebola viruses are cytotoxic because they target cell membrane cholesterol (136), which is affected by statins. Other studies, however, suggest that the host response to Ebola virus infection itself could be a target of treatment.…”

Section: Ebola Virus Diseasementioning

confidence: 99%

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

2016

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There is an ongoing threat of epidemic or pandemic diseases that could be caused by influenza, Ebola or other emerging viruses. It will be difficult and costly to develop new drugs that target each of these viruses. Statins and angiotensin receptor blockers (ARBs) have been effective in treating patients with sepsis, pneumonia and influenza, and a statin/ARB combination appeared to dramatically reduce mortality during the recent Ebola outbreak. These drugs target (among other things) the endothelial dysfunction found in all of these diseases. Most scientists work on new drugs that target viruses, and few accept the idea of treating the host response with generic drugs. A great deal of research will be needed to show conclusively that these drugs work, and this will require the support of public agencies and foundations. Investigators in developing countries should take an active role in this research. If the next Public Health Emergency of International Concern is caused by an emerging virus, a "top down" approach to developing specific new drug treatments is unlikely to be effective. However, a "bottom up" approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could reduce mortality in any country with a basic health care system. In doing so, it would make an immeasurable contribution to global equity and global security.

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Section: Ebola Virus Diseasementioning

confidence: 99%

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

2016

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“…Intriguingly and in contrast to EBOV, MARV infection leads to the activation of cytoprotective responses in infected cells to prolong cell viability (as discussed below) (Page et al 2014;Edwards and Basler 2015;Zhang et al 2014;Johnson et al 2016). -Dany et al 2006;Takada et al 2000;Yang et al 2000;Chan et al 2000;Volchkov et al 2001;Simmons et al 2002;Ray et al 2004;Sullivan et al 2005;Han et al 2007;Francica et al 2009;Hacke et al 2015;Melito et al 2008). The mechanism of cell death in VP40-expressing cells remains undetermined but seems to be related to transient overexpression of the protein (Alazard-Dany et al 2006;Melito et al 2008).…”

Section: In Vitro Analysis Of Filovirus-induced Cell Deathmentioning

confidence: 99%

Filovirus Strategies to Escape Antiviral Responses

Olejnik

Hume

Leung

et al. 2017

Current Topics in Microbiology and Immunology

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This chapter describes the various strategies filoviruses use to escape host immune responses with a focus on innate immune and cell death pathways. Since filovirus replication can be efficiently blocked by interferon (IFN), filoviruses have evolved mechanisms to counteract both type I IFN induction and IFN response signaling pathways. Intriguingly, marburg- and ebolaviruses use different strategies to inhibit IFN signaling. This chapter also summarizes what is known about the role of IFN-stimulated genes (ISGs) in filovirus infection. These fall into three categories: those that restrict filovirus replication, those whose activation is inhibited by filoviruses, and those that have no measurable effect on viral replication. In addition to innate immunity, mammalian cells have evolved strategies to counter viral infections, including the induction of cell death and stress response pathways, and we summarize our current knowledge of how filoviruses interact with these pathways. Finally, this chapter delves into the interaction of EBOV with myeloid dendritic cells and macrophages and the associated inflammatory response, which differs dramatically between these cell types when they are infected with EBOV. In summary, we highlight the multifaceted nature of the host-viral interactions during filoviral infections.

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“…The mucin-like domain, which projects from the top of the GP trimer, acts as a shield to prevent immune recognition of neutralization sites [19] and has also been observed to initiate cell activation and the production of inflammatory cytokines in vitro [12]. The transmembrane (TM) domain tethers the GP trimer to the viral membrane and has been implicated in endothelial cell disruption [15]. The adverse effects of the mucin-like domain and the TM domain could be eliminated in future DNA or subunit vaccine lacking these regions.…”

mentioning

confidence: 99%

“…Expression of full-length GP triggers the extensive formation of filaments at the plasma membrane, followed by cellular detachment. The same effect is seen when only the C-terminal GP2 subunit is expressed but can be partially reversed by mutation within the TM region [15]. Additionally, it is worth noting that a significant portion of GP is shed from the infected cell surface through the activity of a metalloprotease, tumor necrosis factor α-converting enzyme (TACE).…”

mentioning

confidence: 99%