Ebola Hemorrhagic Shock Syndrome-on-a-Chip.
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ABSTRACT:
SUBMITTER: Junaid A
PROVIDER: S-EPMC6941864 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Zaire ebolavirus (ZEBOV) is among the deadliest known human pathogens, causing severe hemorrhagic fever with high case fatality rates ranging from 70-90%. The lack of effective vaccines or treatment available for ZEBOV renders this pathogen as a significant global biodefense threat, as evidenced by the current, highly lethal outbreak of a novel ZEBOV variant in western Africa. Existing mouse models of lethal ZEBOV infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever (EHF) including prolonged blood coagulation, acute hepatitis, disseminated intravascular coagulation (DIC), and death from hemorrhagic shock, thus restricting pathogenesis studies to non-human primates (NHP). This has prevented rapid evaluation of countermeasures in outbreak scenarios, and impeded a comprehensive understanding of how host responses to infection contribute to severe EHF disease. Here we demonstrate that mice from the Collaborative Cross (CC), a panel of reproducible, recombinant inbred animals that span the genetic breadth of three murine subspecies, are susceptible to a spectrum of disease phenotypes following ZEBOV infection. In contrast to C57Bl6/J mice, which develop lethal disease without symptoms of EHF, CC recombinant inbred intercrossed (CC-RIX) lines develop either complete resistance to lethal disease or severe EHF characterized by prolonged coagulation times and 100% mortality. Disease resistance and survival is not dependent on viral tropism, as both resistant and EHF-susceptible lines show similar inflammation and cytopathic effect in target organs. Transcriptomics reveal potential mechanisms for both induction of severe hemorrhage in EHF mediated by IL-6 and vascular activation, and resistance to lethal infection by induction of lymphocyte differentiation and cellular adhesion. These data demonstrate that host responses specific to unique genetic backgrounds determine susceptibility to hemorrhagic syndrome independent of virus replication. The CC represents a novel mouse model for studying EHF pathogenesis, and we anticipate that it will be applied immediately to developing and evaluating therapeutic countermeasures. Microarrays were performed on liver and spleen samples from mice collected at days 1, 3, and 5 post-infection with mouse adapted Zaire ebolavirus or from time-matched mock-infected animals.
2014-05-01 | E-GEOD-57214 | biostudies-arrayexpress
Project description:Zaire ebolavirus (ZEBOV) is among the deadliest known human pathogens, causing severe hemorrhagic fever with high case fatality rates ranging from 70-90%. The lack of effective vaccines or treatment available for ZEBOV renders this pathogen as a significant global biodefense threat, as evidenced by the current, highly lethal outbreak of a novel ZEBOV variant in western Africa. Existing mouse models of lethal ZEBOV infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever (EHF) including prolonged blood coagulation, acute hepatitis, disseminated intravascular coagulation (DIC), and death from hemorrhagic shock, thus restricting pathogenesis studies to non-human primates (NHP). This has prevented rapid evaluation of countermeasures in outbreak scenarios, and impeded a comprehensive understanding of how host responses to infection contribute to severe EHF disease. Here we demonstrate that mice from the Collaborative Cross (CC), a panel of reproducible, recombinant inbred animals that span the genetic breadth of three murine subspecies, are susceptible to a spectrum of disease phenotypes following ZEBOV infection. In contrast to C57Bl6/J mice, which develop lethal disease without symptoms of EHF, CC recombinant inbred intercrossed (CC-RIX) lines develop either complete resistance to lethal disease or severe EHF characterized by prolonged coagulation times and 100% mortality. Disease resistance and survival is not dependent on viral tropism, as both resistant and EHF-susceptible lines show similar inflammation and cytopathic effect in target organs. Transcriptomics reveal potential mechanisms for both induction of severe hemorrhage in EHF mediated by IL-6 and vascular activation, and resistance to lethal infection by induction of lymphocyte differentiation and cellular adhesion. These data demonstrate that host responses specific to unique genetic backgrounds determine susceptibility to hemorrhagic syndrome independent of virus replication. The CC represents a novel mouse model for studying EHF pathogenesis, and we anticipate that it will be applied immediately to developing and evaluating therapeutic countermeasures.
2014-05-01 | GSE57214 | GEO
Project description:Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs.
| S-EPMC3532827 | biostudies-other
Project description:BackgroundEbola hemorrhagic fever (EHF) outbreaks occur sporadically in Africa and result in high rates of death. The 2000-2001 outbreak of Sudan virus-associated EHF in the Gulu district of Uganda led to 425 cases, of which 216 were laboratory confirmed, making it the largest EHF outbreak on record. Serum specimens from this outbreak had been preserved in liquid nitrogen from the time of collection and were available for analysis.MethodsAvailable samples were tested using a series of multiplex assays to measure the concentrations of 55 biomarkers. The data were analyzed to identify statistically significant associations between the tested biomarkers and hemorrhagic manifestations, viremia, and/or death.ResultsDeath, hemorrhage, and viremia were independently associated with elevated levels of several chemokines and cytokines. Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator. Finally, samples from nonfatal cases had higher levels of sCD40L.ConclusionsThese novel associations provide a better understanding of EHF pathophysiology and a starting point for researching new potential targets for therapeutic interventions.
| S-EPMC4172044 | biostudies-literature
Project description:Ebola (EBOV) virus causes severe and often lethal hemorrhagic fever in humans and nonhuman primates (NHP), and has been classified as a Category A bioweapon agent. There are currently no approved preventive vaccines or postexposure treatments for EBOV hemorrhagic fever. The mechanisms of EBOV pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in levels of circulating proinflammatory cytokines, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. Identification of effective treatment strategies may greatly benefit based on identification of molecular features of the host response to infection and treatment. In order to identify these gene signatures related to correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected NHP responding to candidate therapeutics. With this approach, we have identified genes that appear to correlate with survival, including chemokine ligand 8 (CCL8/MCP-2), and revealed a subset of distinctly differently expressed genes that may provide possible targets for future diagnostics or therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection as well as identify improved therapeutic strategies. Transcriptional analysis of global gene expression changes in Zaire Ebola Virus (ZEBOV)-infected rhesus macaques that were treated with either recombinant nematode anticoagulant protein c2 (rNAPc2) or recombinant human activated protein C (rhAPC). Animals were infected with 1000pfu ZEBOV, then subsequently treated with rNAPc2 or rhAPC. Four animals were left untreated for controls. Blood samples were taken at specified days post-infection and PBMCs were isolated from the samples and inactivated in TRIzol reagent. Total RNA was isolated from the samples, then linearly amplified and hybridized to a whole genome long-oligonucleotide microarray in a two color comparative format with a commercially available human reference RNA from Stratagene as a consistent control in dataset comparisons.
2010-11-30 | E-GEOD-24943 | biostudies-arrayexpress
Project description:Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
| S-EPMC4241145 | biostudies-literature
Project description:A shotgun label-free quantitative proteomic approach was utilized to compare the peptidome of plasma samples from healthy and hemorrhagic shock pigs to verify the possible role of uncontrolled proteolytic activity in shock.
2021-09-08 | PXD008018 | Pride
Project description:BackgroundPhosphatidylserine (PS) is a key cell membrane phospholipid normally maintained on the inner cell surface but externalizes to the outer surface in response to cellular stress. We hypothesized that PS exposure mediates organ dysfunction in hemorrhagic shock. Our aims were to evaluate PS blockade on (1) pulmonary, (2) renal, and (3) gut function, as well as (4) serum lysophosphatidic acid (LPA), an inflammatory mediator generated by PS externalization, as a possible mechanism mediating organ dysfunction.Materials and methodsRats were either (1) monitored for 130 min (controls, n = 3), (2) hemorrhaged then resuscitated (hemorrhage only group, n = 3), or (3) treated with Diannexin (DA), a PS blocking agent, followed by hemorrhage and resuscitation (DA + hemorrhage group, n = 4). Pulmonary dysfunction was assessed by arterial partial pressure of oxygen, renal dysfunction by serum creatinine, and gut dysfunction by mesenteric endothelial permeability (LP). LPA levels were measured in all groups.ResultsPulmonary: there was no difference in arterial partial pressure of oxygen between groups. Renal: after resuscitation, creatinine levels were lower after PS blockade with DA versus hemorrhage only group (P = 0.01). Gut: LP was decreased after PS blockade with DA versus hemorrhage only group (P < 0.01). Finally, LPA levels were also lower after PS blockade with DA versus the hemorrhage only group but higher than the control group (P < 0.01).ConclusionsPS blockade with DA decreased renal and gut dysfunction associated with hemorrhagic shock and attenuated the magnitude of LPA generation. Our findings suggest potential for therapeutic targets in the future that could prevent organ dysfunction associated with hemorrhagic shock.
| S-EPMC6900439 | biostudies-literature
Project description:Stimulator of IFN genes (STING) activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to produce type I IFNs. Extracellular cold-inducible RNA-binding protein (eCIRP) is released from cells during hemorrhagic shock (HS). We hypothesized that eCIRP activates STING to induce inflammation and acute lung injury (ALI) after HS. WT and STING-/- mice underwent controlled hemorrhage by bleeding, followed by fluid resuscitation. Blood and lungs were collected at 4 hours after resuscitation. Serum ALT, AST, LDH, IL-6, and IFN-β were significantly decreased in STING-/- mice compared with WT mice after HS. In STING-/- mice, the levels of pTBK1 and pIRF3, and expression of TNF-α, IL-6, and IL-1β mRNAs and proteins in the lungs, were significantly decreased compared with WT HS mice. The 10-day mortality rate in STING-/- mice was significantly reduced. I.v. injection of recombinant mouse CIRP (rmCIRP) in STING-/- mice showed a significant decrease in pTBK1 and pIRF3 and in IFN-α and IFN-β mRNAs and proteins in the lungs compared with rmCIRP-treated WT mice. Treatment of TLR4-/-, MyD88-/-, and TRIF-/- macrophages with rmCIRP significantly decreased pTBK1 and pIRF3 levels and IFN-α and IFN-β mRNAs and proteins compared with WT macrophages. HS increases eCIRP levels, which activate STING through TLR4/MyD88/TRIF pathways to exacerbate inflammation.
| S-EPMC8410031 | biostudies-literature
Project description:Ebola (EBOV) virus causes severe and often lethal hemorrhagic fever in humans and nonhuman primates (NHP), and has been classified as a Category A bioweapon agent. There are currently no approved preventive vaccines or postexposure treatments for EBOV hemorrhagic fever. The mechanisms of EBOV pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in levels of circulating proinflammatory cytokines, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. Identification of effective treatment strategies may greatly benefit based on identification of molecular features of the host response to infection and treatment. In order to identify these gene signatures related to correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected NHP responding to candidate therapeutics. With this approach, we have identified genes that appear to correlate with survival, including chemokine ligand 8 (CCL8/MCP-2), and revealed a subset of distinctly differently expressed genes that may provide possible targets for future diagnostics or therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection as well as identify improved therapeutic strategies.
2010-11-30 | GSE24943 | GEO