Treatment of Ebola virus infections with inhibitors of TLR4

Denner, Joachim

doi:10.1016/j.mehy.2015.05.009

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…This rapid turnover may account for the projected high levels of sGP in the tissues and blood of infected animals [7]. EBOV GP and LPS have also been suggested to compete for the same receptor, TLR4; a possible attachment factor for the virus [7,13,38], which is expressed on macrophages. Whether the secreted, truncated version of GP may also bind to TLR4 is unknown.…”

Section: Discussionmentioning

confidence: 99%

Ebola virus secreted glycoprotein decreases the anti-viral immunity of macrophages in early inflammatory responses

Bradley

Harrison

Corey

et al. 2018

Cellular Immunology

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During Ebola virus (EBOV) infection, secreted glycoprotein (sGP) is found in large quantities in the serum of both patients and infected animal models. It is thought to serve as a decoy for anti-EBOV antibodies. Using an in vitro model incorporating treatment of non-infected human THP-1 macrophages with recombinant EBOV sGP, this study sought to examine the impact of sGP upon key macrophage functions. Macrophage polarization and phagocytic capacity of activated macrophages were found to be unaltered by sGP treatment. However, treatment with sGP inhibited macrophage production of the pro-inflammatory cytokines TNFα and IL-6 while the yield of anti-inflammatory cytokine, IL-10, remained intact. Interestingly, the migratory ability of macrophages was also diminished by sGP, potentially due to a decrease in expression of CD11b, a vital macrophage integrin. Thus, EBOV sGP may operate to diminish functional contributions of non-infected macrophages to increase the potential viral dissemination.

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Section: Discussionmentioning

confidence: 99%

Ebola virus secreted glycoprotein decreases the anti-viral immunity of macrophages in early inflammatory responses

Bradley

Harrison

Corey

et al. 2018

Cellular Immunology

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“…However, in the context of infection, dampening TLR4 activation may be beneficial. Thus, research into the use of TLR4 inhibitors in the treatment of EBOV infection has been recommended ( Denner, 2015 ). In animal models of sepsis, dampening TLR-induced inflammation led to reduced sepsis progression.…”

Section: Potential For Therapeutic Applicationsmentioning

confidence: 99%

Activation of TLR4 by viral glycoproteins: A double-edged sword?

et al. 2022

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Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to viral infection. However, an unbalanced proinflammatory response can be detrimental to the host. Recently, multiple studies have identified that the SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in the induction of proinflammatory cytokine expression. Activation of TLR4 by viral glycoproteins has also been observed in the context of other viral infection models, including respiratory syncytial virus (RSV), dengue virus (DENV) and Ebola virus (EBOV). However, the mechanisms involved in virus-TLR4 interactions have remained unclear. Here, we review viral glycoproteins that act as pathogen-associated molecular patterns to induce an immune response via TLR4. We explore the current understanding of the mechanisms underlying how viral glycoproteins are recognized by TLR4 and discuss the contribution of TLR4 activation to viral pathogenesis. We identify contentious findings and research gaps that highlight the importance of understanding viral glycoprotein-mediated TLR4 activation for potential therapeutic approaches.

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“…TLR4 binding leads to cellular activation and the potent induction of inflammatory responses [12]. Given TLR4 activation has been linked directly to vascular leak in other viral systems [13], a central role for this pathway in EBOV pathology remains an untested but likely hypothesis [14]. …”

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confidence: 99%