Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A mouse model for MERS coronavirus-induced acute respiratory distress syndrome.

ABSTRACT: Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR-Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.

SUBMITTER: Cockrell AS

PROVIDER: S-EPMC5578707 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Genetically Engineering a Susceptible Mouse Model for MERS-CoV-Induced Acute Respiratory Distress Syndrome.

Project description:Since 2012, monthly cases of Middle East respiratory syndrome coronavirus (MERS-CoV) continue to cause severe respiratory disease that is fatal in ~35% of diagnosed individuals. The ongoing threat to global public health and the need for novel therapeutic countermeasures have driven the development of animal models that can reproducibly replicate the pathology associated with MERS-CoV in human infections. The inability of MERS-CoV to replicate in the respiratory tracts of mice, hamsters, and ferrets stymied initial attempts to generate small animal models. Identification of human dipeptidyl peptidase IV (hDPP4) as the receptor for MERS-CoV infection opened the door for genetic engineering of mice. Precise molecular engineering of mouse DPP4 (mDPP4) with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology maintained inherent expression profiles, and limited MERS-CoV susceptibility to tissues that naturally express mDPP4, notably the lower respiratory tract wherein MERS-CoV elicits severe pulmonary pathology. Here, we describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330), and the use of adaptive evolution to generate novel MERS-CoV isolates that cause fatal respiratory disease. The 288-330+/+ mice are currently being used to evaluate novel drug, antibody, and vaccine therapeutic countermeasures for MERS-CoV. The chapter starts with a historical perspective on the emergence of MERS-CoV and animal models evaluated for MERS-CoV pathogenesis, and then outlines the development of the 288-330+/+ mouse model, assays for assessing a MERS-CoV pulmonary infection in a mouse model, and describes some of the challenges associated with using genetically engineered mice.

| S-EPMC7123801 | biostudies-literature

A mouse model for SARS-CoV-2-induced acute respiratory distress syndrome.

Project description: Not available

| S-EPMC7775436 | biostudies-literature

A novel tree shrew model of lipopolysaccharide-induced acute respiratory distress syndrome.

Project description:IntroductionAcute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure, with substantial attributable morbidity and mortality. The small animal models that are currently used for ARDS do not fully manifest all of the pathological hallmarks of human patients, which hampers both the studies of disease mechanism and drug development.ObjectivesTo examine whether the phenotypic changes of primate-like tree shrews in response to a one-hit lipopolysaccharides (LPS) injury resemble human ARDS features.MethodsLPS was administered to tree shrews through intratracheal instillation; then, the animals underwent CT or PET/CT imaging to examine the changes in the structure and function of the whole lung. The lung histology was analyzed by H&E staining and immunohistochemical staining of inflammatory cells.ResultsResults demonstrated that tree shrews exhibited an average survival time of 3-5 days after LPS insult, as well as an obvious symptom of dyspnea before death. The ratios of PaO2 to FiO2 (P/F ratio) were close to those of moderate ARDS in humans. CT imaging showed that the scope of the lung injury in tree shrews after LPS treatment were extensive. PET/CT imaging with 18F-FDG displayed an obvious inflammatory infiltration. Histological analysis detected the formation of a hyaline membrane, which is usually present in human ARDS.ConclusionThis study established a lung injury model with a primate-like small animal model and confirmed that they have similar features to human ARDS, which might provide a valuable tool for translational research.

| S-EPMC10834818 | biostudies-literature

Transcriptional responses of Middle East respiratory syndrome coronavirus (MERS-CoV) in marmosets

Project description:The absence of a robust disease model currently hinders the evaluation of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV that results in mild-to-moderate disease has been utilized to describe the pathogenesis of this virus and for the evaluation of therapeutics, the inability to produce uniform disease with substantial virus replication complicates analysis in countermeasure studies. In an attempt to identify a more robust disease model, DPP4 sequences of various non-human primates were aligned. Modeling of the interactions between the receptor binding domain of MERS-CoV and its cognate receptor DPP4 predicted a "good fit" with complete conservation of all of the critical residues. To determine the feasibility of the marmoset as a MERS-CoV disease model, common marmosets were inoculated with MERS-CoV via combined intratracheal, intranasal, oral and ocular routes. Marmosets developed signs of moderate to severe illness with progressive serious to severe pneumonia. Progressive gross lesions were evident in animals necropsied at 3, 4 and 6 days post inoculation and two animals were euthanized during the study due to disease severity. This is the first description of a moderate-to-severe, with potentially lethality, disease model of MERS-CoV and as such will have utility for vaccine and other countermeasure efficacy evaluations in addition to further pathogenesis studies. Lung tissue samples were isolated and sequenced at 3, 4 and 6 days post inoculation. Two animals were euthanized during the study due to disease severity.

2014-06-10 | E-GEOD-55023 | biostudies-arrayexpress

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease.

Project description:This review describes targeting neutrophils as a potential therapeutic strategy for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutrophil counts are significantly elevated in patients with COVID-19 and significantly correlated with disease severity. The neutrophil-to-lymphocyte ratio can serve as a clinical marker for predicting fatal complications related to ARDS in patients with COVID-19. Neutrophil-associated inflammation plays a critical pathogenic role in ARDS. The effector functions of neutrophils, acting as respiratory burst oxidants, granule proteases, and neutrophil extracellular traps, are linked to the pathogenesis of ARDS. Hence, neutrophils can not only be used as pathogenic markers but also as candidate drug targets for COVID-19 associated ARDS.

| S-EPMC7583590 | biostudies-literature

Middle East respiratory syndrome (MERS) coronavirus and dromedaries.

Project description:Middle East Respiratory Syndrome (MERS) is a zoonotic viral disease that can be transmitted from dromedaries to human beings. More than 1500 cases of MERS have been reported in human beings to date. Although MERS has been associated with 30% case fatality in human beings, MERS coronavirus (MERS-CoV) infection in dromedaries is usually asymptomatic. In rare cases, dromedaries may develop mild respiratory signs. No MERS-CoV or antibodies against the virus have been detected in camelids other than dromedaries. MERS-CoV is mainly acquired in dromedaries when they are less than 1 year of age, and the proportion of seropositivity increases with age to a seroprevalence of 100% in adult dromedaries. Laboratory diagnosis of MERS-CoV infection in dromedaries can be achieved through virus isolation using Vero cells, RNA detection by real-time quantitative reverse transcriptase-PCR and antigen detection using respiratory specimens or serum. Rapid nucleocapsid antigen detection using a lateral flow platform allows efficient screening of dromedaries carrying MERS-CoV. In addition to MERS-CoV, which is a lineage C virus in the Betacoronavirus (betaCoV) genus, a lineage B betaCoV and a virus in the Alphacoronavirus (alphaCoV) genus have been detected in dromedaries. Dromedary CoV UAE-HKU23 is closely related to human CoV OC43, whereas the alphaCoV has not been detected in human beings to date.

| S-EPMC7110516 | biostudies-literature

Transcriptional responses of Middle East respiratory syndrome coronavirus (MERS-CoV) in marmosets

2014-06-10 | GSE55023 | GEO

Transcriptomic Analysis Of The Novel Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-06-10 | GSE56189 | GEO

Acute respiratory distress syndrome.

Project description:Acute respiratory distress syndrome (ARDS) is an acute respiratory illness characterised by bilateral chest radiographical opacities with severe hypoxaemia due to non-cardiogenic pulmonary oedema. The COVID-19 pandemic has caused an increase in ARDS and highlighted challenges associated with this syndrome, including its unacceptably high mortality and the lack of effective pharmacotherapy. In this Seminar, we summarise current knowledge regarding ARDS epidemiology and risk factors, differential diagnosis, and evidence-based clinical management of both mechanical ventilation and supportive care, and discuss areas of controversy and ongoing research. Although the Seminar focuses on ARDS due to any cause, we also consider commonalities and distinctions of COVID-19-associated ARDS compared with ARDS from other causes.

| S-EPMC8248927 | biostudies-literature

Acute respiratory distress syndrome.

Project description:The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

| S-EPMC6709677 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data