scholarly journals Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

2017 ◽  
Vol 91 (11) ◽  
Author(s):  
Judith Olejnik ◽  
Adriana Forero ◽  
Laure R. Deflubé ◽  
Adam J. Hume ◽  
Whitney A. Manhart ◽  
...  
Keyword(s):  
Host Response ◽  
Ebola Virus ◽  
Severe Disease ◽  
Health Concern ◽  
Type I ◽  
Proinflammatory Response ◽  
Tlr4 Signaling ◽  
Human Macrophages ◽  
Ebov Infection ◽  
Reston Virus

ABSTRACT Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease. IMPORTANCE Emerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV- and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.

scholarly journals Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Mike Flint ◽  
Éric Bergeron ◽  
Anita K. McElroy ◽  
Payel Chatterjee ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Statin Treatment ◽  
Ebola Virus Disease ◽  
Health Concern ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Antiviral Effects ◽  
Ebov Infection ◽  
Glycoprotein Processing

ABSTRACTEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infectionin vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCETreatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

scholarly journals Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus

2020 ◽  
Vol 8 (8) ◽  
pp. 1215
Author(s):  
Bianca S. Bodmer ◽  
Josephin Greßler ◽  
Marie L. Schmidt ◽  
Julia Holzerland ◽  
Janine Brandt ◽  
...  
Keyword(s):  
Life Cycle ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Severe Disease ◽  
Case Fatality ◽  
Viral Rna ◽  
Pathogenic Potential ◽  
Rnp Complex ◽  
Reston Virus

Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture.

scholarly journals Ebola virus infection induces a type I interferon response and the shutdown of key liver functions in human iPSC-derived hepatocytes

2021 ◽  
Author(s):  
Whitney Manhart ◽  
Liliana Mancio ◽  
Ellen Suder ◽  
Carlos Villacorta-Martin ◽  
Jonathan Lindstrom-Vautrin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ebola Virus ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Liver Functions ◽  
Ebov Infection ◽  
Transcriptomic Changes ◽  
Human Ipsc ◽  
Ebola Virus Infection

Abstract Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to the observed inflammatory response. Here, we present an iPSC-derived hepatocyte platform to define the hepato-intrinsic response to EBOV infection. Transcriptomics analysis revealed a delayed host response with minimal transcriptomic changes at one day post infection (dpi) followed by a general downregulation of genes associated with hepatic functions and upregulation of interferon signaling at two and three dpi. Using RNA-FISH, we showed at single cell resolution that IFNβ and CXCL10 were mainly expressed in bystander cells or cells with weak EBOV mRNA signal intensity. We did not observe an inflammatory signature at any timepoint. In conclusion, iPSC-derived hepatocytes are an immune competent platform to study intrinsic responses to EBOV infection that have not been observed in EBOV-infected hepatocarcinoma cell lines.

scholarly journals Genetically diverse mouse models of SARS-CoV-2 infection model clinical variation and cytokine responses in COVID-19

2021 ◽  
Author(s):  
Shelly Robertson ◽  
Olivia Bedard ◽  
Kristin McNally ◽  
Matthew Lewis ◽  
Chad Clancy ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Severe Disease ◽  
Infection Model ◽  
Human Populations ◽  
Type I ◽  
Significant Determinant ◽  
Proinflammatory Response ◽  
Infection Dynamics ◽  
F1 Progeny ◽  
Clinical Variation

Host genetics are a significant determinant of coronavirus disease 2019 (COVID-19). Animal models that reflect genetic diversity and a range of clinical outcomes observed in human populations are needed to understand mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dynamics and disease. Here, we report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross (CC) founder strains crossed to C57BL/6J mice expressing the K18-hACE2 transgene3 that enables infection by SARS-CoV-2. Infection of CCxK18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, survival was closely associated with early type I interferon expression and a phased proinflammatory response distinct from mice with severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mice that provide a genetically tractable platform for understanding antiviral immunity and evaluating countermeasures.

scholarly journals Quercetin Blocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory Function

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Elisa Fanunza ◽  
Mathieu Iampietro ◽  
Simona Distinto ◽  
Angela Corona ◽  
Marina Quartu ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Hemorrhagic Fever ◽  
Type I ◽  
Virulence Determinants ◽  
Inhibitory Function ◽  
Viral Binding ◽  
Ebov Infection ◽  
Small Set ◽  
Tight Correlation ◽  
Ebola Virus Infection

ABSTRACT Ebola virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The epidemics from 2013 to 2016 resulted in more than 11,000 deaths, and another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type I interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking the IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort to find novel EBOV inhibitors, a screening of a small set of flavonoids was performed; it showed that quercetin and wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, quercetin, showing a half-maximal inhibitory concentration (IC50) of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN gene transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.

scholarly journals HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain

2015 ◽  
Vol 112 (50) ◽  
pp. E6937-E6944 ◽  
Author(s):  
Douglas R. Wilcox ◽  
William J. Muller ◽  
Richard Longnecker
Keyword(s):  
Host Response ◽  
Severe Disease ◽  
Mutant Virus ◽  
Slice Culture ◽  
Type I ◽  
Type I Ifn ◽  
Newborn Mice ◽  
Disseminated Disease ◽  
The Brain ◽  
Hsv 1

Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.

scholarly journals A Single Phosphorodiamidate Morpholino Oligomer Targeting VP24 Protects Rhesus Monkeys against Lethal Ebola Virus Infection

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Travis K. Warren ◽  
Chris A. Whitehouse ◽  
Jay Wells ◽  
Lisa Welch ◽  
Alison E. Heald ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Ebola Virus ◽  
Severe Disease ◽  
The United States ◽  
African Countries ◽  
Primate Model ◽  
Promising Target ◽  
Significant Survival ◽  
Ebov Infection ◽  
Phosphorodiamidate Morpholino Oligomers

ABSTRACT Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures. IMPORTANCE Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval.

Stem Cell-Based Therapies: A New Ray of Hope for Diabetic Patients

2019 ◽  
Vol 14 (2) ◽  
pp. 146-151 ◽  
Author(s):  
Junaid Khan ◽  
Amit Alexander ◽  
Mukta Agrawal ◽  
Ajazuddin ◽  
Sunil Kumar Dubey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Drug Therapy ◽  
Type I Diabetes ◽  
Embryonic Stem ◽  
Health Concern ◽  
Future Research ◽  
Diabetic Patients ◽  
Successful Implementation ◽  
Type I

Diabetes and its complications are a significant health concern throughout the globe. There are physiological differences in the mechanism of type-I and type-II diabetes and the conventional drug therapy as well as insulin administration seem to be insufficient to address the problem at large successfully. Hypoglycemic swings, frequent dose adjustments and resistance to the drug are major problems associated with drug therapy. Cellular approaches through stem cell based therapeutic interventions offer a promising solution to the problem. The need for pancreatic transplants in case of Type- I diabetes can also be by-passed/reduced due to the formation of insulin producing β cells via stem cells. Embryonic Stem Cells (ESCs) and induced Pluripotent Stem Cells (iPSCs), successfully used for generating insulin producing β cells. Although many experiments have shown promising results with stem cells in vitro, their clinical testing still needs more exploration. The review attempts to bring into light the clinical studies favoring the transplantation of stem cells in diabetic patients with an objective of improving insulin secretion and improving degeneration of different tissues in response to diabetes. It also focuses on the problems associated with successful implementation of the technique and possible directions for future research.

scholarly journals Charged Residues Flanking the Transmembrane Domain of Two Related Toxin–Antitoxin System Toxins Affect Host Response

Toxins ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 329
Author(s):  
Andrew Holmes ◽  
Jessie Sadlon ◽  
Keith Weaver
Keyword(s):  
Amino Acid ◽  
Enterococcus Faecalis ◽  
Host Response ◽  
Cytoplasmic Membrane ◽  
Transmembrane Domain ◽  
The Other ◽  
Type I ◽  
Transcriptomic Response ◽  
Specific Amino Acid ◽  
Transporter Protein

A majority of toxins produced by type I toxin–antitoxin (TA-1) systems are small membrane-localized proteins that were initially proposed to kill cells by forming non-specific pores in the cytoplasmic membrane. The examination of the effects of numerous TA-1 systems indicates that this is not the mechanism of action of many of these proteins. Enterococcus faecalis produces two toxins of the Fst/Ldr family, one encoded on pheromone-responsive conjugative plasmids (FstpAD1) and the other on the chromosome, FstEF0409. Previous results demonstrated that overexpression of the toxins produced a differential transcriptomic response in E. faecalis cells. In this report, we identify the specific amino acid differences between the two toxins responsible for the differential response of a gene highly induced by FstpAD1 but not FstEF0409. In addition, we demonstrate that a transporter protein that is genetically linked to the chromosomal version of the TA-1 system functions to limit the toxicity of the protein.

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