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

Bradley, Jillian H.; Harrison, Ametria; Corey, Ashley; Gentry, Nathan; Gregg, Randal K.

doi:10.1016/j.cellimm.2017.11.009

Cited by 18 publications

(16 citation statements)

References 41 publications

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“…This also ensures that we may capture compounds that have host effects as well as direct effects on the virus 68 which in vitro pseudovirus and VLP entry would fail to capture. This may also be important as it becomes increasingly recognized how EBOV manipulates the immune response in macrophages, 69 and we may need to identify compounds that have an effect on the host.…”

Section: Discussionmentioning

confidence: 99%

Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

et al. 2019

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We have previously described the first Bayesian machine learning models from FDA-approved drug screens, for identifying compounds active against the Ebola virus (EBOV). These models led to the identification of three active molecules in vitro: tilorone, pyronaridine, and quinacrine. A follow-up study demonstrated that one of these compounds, tilorone, has 100% in vivo efficacy in mice infected with mouse-adapted EBOV at 30 mg/kg/day intraperitoneal. This suggested that we can learn from the published data on EBOV inhibition and use it to select new compounds for testing that are active in vivo. We used these previously built Bayesian machine learning EBOV models alongside our chemical insights for the selection of 12 molecules, absent from the training set, to test for in vitro EBOV inhibition. Nine molecules were directly selected using the model, and eight of these molecules possessed a promising in vitro activity (EC50 < 15 μM). Three further compounds were selected for an in vitro evaluation because they were antimalarials, and compounds of this class like pyronaridine and quinacrine have previously been shown to inhibit EBOV. We identified the antimalarial drug arterolane (IC50 = 4.53 μM) and the anticancer clinical candidate lucanthone (IC50 = 3.27 μM) as novel compounds that have EBOV inhibitory activity in HeLa cells and generally lack cytotoxicity. This work provides further validation for using machine learning and medicinal chemistry expertize to prioritize compounds for testing in vitro prior to more costly in vivo tests. These studies provide further corroboration of this strategy and suggest that it can likely be applied to other pathogens in the future.

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Section: Discussionmentioning

confidence: 99%

Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

et al. 2019

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“…Current literature on HCWs and serological testing for ebolaviruses (for evidence of exposure) is restricted mainly to anti-glycoprotein (GP) antibody, the viral protein critical for attachment to and penetration of host cells. Because of its positioning on the virion surface, GP is a target of neutralizing antibodies and has been frequently studied as a target for vaccines and other therapeutics [22,[25][26][27]. Furthermore, Richardson et al suggest limiting the definition of EBOV seropositivity to anti-GP reactivity based on a comparison of anti-GP and anti-nucleoprotein (NP) antibody responses [28].…”

mentioning

confidence: 99%

Serologic Markers for Ebolavirus Among Healthcare Workers in the Democratic Republic of the Congo

Hoff

Mukadi²,

Doshi

et al. 2018

The Journal of Infectious Diseases

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Healthcare settings have played a major role in propagation of Ebola virus (EBOV) outbreaks. Healthcare workers (HCWs) have elevated risk of contact with EBOV-infected patients, particularly if safety precautions are not rigorously practiced. We conducted a serosurvey to determine seroprevalence against multiple EBOV antigens among HCWs of Boende Health Zone, Democratic Republic of the Congo, the site of a 2014 EBOV outbreak. Interviews and specimens were collected from 565 consenting HCWs. Overall, 234 (41.4%) of enrolled HCWs were reactive to at least 1 EBOV protein: 159 (28.1%) were seroreactive for anti-glycoprotein immunoglobulin G (IgG), 89 (15.8%) were seroreactive for anti-nucleoprotein IgG, and 54 (9.5%) were VP40 positive. Additionally, sera from 16 (2.8%) HCWs demonstrated neutralization capacity. These data demonstrate that a significant proportion of HCWs have the ability to neutralize virus, despite never having developed Ebola virus disease symptoms, highlighting an important and poorly documented aspect of EBOV infection and progression.

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“…Rapid antiviral innate immunity may also be mediated by EBOV-GP, which has been shown to induce activation of human macrophages and DCs via TLR4 signaling [ 158 , 159 , 160 , 161 ]. This effect of membrane-bound GP (predominant form during vaccination) is distinct from the effects of soluble GP (sGP), which is produced in large quantities during EBOV infection: for instance, in vitro stimulation of DCs and macrophages with sGP thwarts migratory ability and induces a robust cytokine response while simultaneously increasing vascular permeability [ 4 , 162 , 163 ]. Whereas TLR4 stimulation has been shown to activate DCs and macrophages to differentiate and macrophages to polarize into an anti-inflammatory state [ 6 , 109 , 158 , 161 , 164 , 165 , 166 , 167 ].…”

Section: Rvsv-ebov-gp and Rapid Protection: The Role Of Innate Immmentioning

confidence: 99%

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity

Pinski

Messaoudi

2020

Microorganisms

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Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity.

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

Cited by 18 publications

References 41 publications

Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

Serologic Markers for Ebolavirus Among Healthcare Workers in the Democratic Republic of the Congo

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity

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