Vasculitis and Neutrophil Extracellular Traps in Lungs of Golden Syrian Hamsters With SARS-CoV-2

Neutrophil extracellular traps (NETs) have been identified as one pathogenetic trigger in severe COVID-19 cases and therefore well-described animal models to understand the influence of NETs in COVID-19 pathogenesis are needed. SARS-CoV-2 infection causes infection and interstitial pneumonia of varying severity in humans and COVID-19 models. Pulmonary as well as peripheral vascular lesions represent a severe, sometimes fatal, disease complication of unknown pathogenesis in COVID-19 patients. Furthermore, neutrophil extracellular traps (NETs), which are known to contribute to vessel inflammation or endothelial damage, have also been shown as potential driver of COVID-19 in humans. Though most studies in animal models describe the pulmonary lesions characterized by interstitial inflammation, type II pneumocyte hyperplasia, edema, fibrin formation and infiltration of macrophages and neutrophils, detailed pathological description of vascular lesions or NETs in COVID-19 animal models are lacking so far. Here we report different types of pulmonary vascular lesions in the golden Syrian hamster model of COVID-19. Vascular lesions included endothelialitis and vasculitis at 3 and 6 days post infection (dpi), and were almost nearly resolved at 14 dpi. Importantly, virus antigen was present in pulmonary lesions, but lacking in vascular alterations. In good correlation to these data, NETs were detected in the lungs of infected animals at 3 and 6 dpi. Hence, the Syrian hamster seems to represent a useful model to further investigate the role of vascular lesions and NETs in COVID-19 pathogenesis.

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Effect of intestinal alkalinization on irinotecan (CPT-11)-induced diarrhea in the golden Syrian hamster model

Gastroenterology ◽

10.1016/s0016-5085(01)83047-x ◽

2001 ◽

Vol 120 (5) ◽

pp. A613-A613

Author(s):

T IKEGAMI ◽

P LATHAM ◽

K KOBAYASHI ◽

K ARIMORI ◽

B BOUSCAREL

Keyword(s):

Syrian Hamster ◽

Hamster Model ◽

Golden Syrian Hamster

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The SARS-CoV-2 Omicron (B.1.1.529) variant exhibits altered pathogenicity, transmissibility, and fitness in the golden Syrian hamster model

10.1101/2022.01.12.476031 ◽

2022 ◽

Author(s):

Shuofeng Yuan ◽

Zi-Wei Ye ◽

Ronghui Liang ◽

Kaiming Tang ◽

Anna Jinxia Zhang ◽

...

Keyword(s):

Syrian Hamster ◽

Neutralizing Antibodies ◽

Selection Pressure ◽

Immune Selection ◽

Hamster Model ◽

Golden Syrian Hamster ◽

New Variant ◽

Contact Transmission

The newly emerging SARS-CoV-2 Omicron (B.1.1.529) variant first identified in South Africa in November 2021 is characterized by an unusual number of amino acid mutations in its spike that renders existing vaccines and therapeutic monoclonal antibodies dramatically less effective. The in vivo pathogenicity, transmissibility, and fitness of this new Variant of Concerns are unknown. We investigated these virological attributes of the Omicron variant in comparison with those of the currently dominant Delta (B.1.617.2) variant in the golden Syrian hamster COVID-19 model. Omicron-infected hamsters developed significantly less body weight losses, clinical scores, respiratory tract viral burdens, cytokine/chemokine dysregulation, and tissue damages than Delta-infected hamsters. The Omicron and Delta variant were both highly transmissible (100% vs 100%) via contact transmission. Importantly, the Omicron variant consistently demonstrated about 10-20% higher transmissibility than the already-highly transmissible Delta variant in repeated non-contact transmission studies (overall: 30/36 vs 24/36, 83.3% vs 66.7%). The Delta variant displayed higher fitness advantage than the Omicron variant without selection pressure in both in vitro and in vivo competition models. However, this scenario drastically changed once immune selection pressure with neutralizing antibodies active against the Delta variant but poorly active against the Omicron variant were introduced, with the Omicron variant significantly outcompeting the Delta variant. Taken together, our findings demonstrated that while the Omicron variant is less pathogenic than the Delta variant, it is highly transmissible and can outcompete the Delta variant under immune selection pressure. Next-generation vaccines and antivirals effective against this new VOC are urgently needed.

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Surgical Mask Partition Reduces the Risk of Noncontact Transmission in a Golden Syrian Hamster Model for Coronavirus Disease 2019 (COVID-19)

Clinical Infectious Diseases ◽

10.1093/cid/ciaa644 ◽

2020 ◽

Vol 71 (16) ◽

pp. 2139-2149 ◽

Cited By ~ 41

Author(s):

Jasper Fuk-Woo Chan ◽

Shuofeng Yuan ◽

Anna Jinxia Zhang ◽

Vincent Kwok-Man Poon ◽

Chris Chung-Sing Chan ◽

...

Keyword(s):

Experimental Evidence ◽

Syrian Hamster ◽

Antigen Expression ◽

Hamster Model ◽

Golden Syrian Hamster ◽

Healthcare Settings ◽

Clinical Scoring ◽

Respiratory Droplets ◽

Viral Nucleocapsid

Abstract Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be mostly transmitted by medium- to large-sized respiratory droplets, although airborne transmission may be possible in healthcare settings involving aerosol-generating procedures. Exposure to respiratory droplets can theoretically be reduced by surgical mask usage. However, there is a lack of experimental evidence supporting surgical mask usage for prevention of COVID-19. Methods We used a well-established golden Syrian hamster SARS-CoV-2 model. We placed SARS-CoV-2-challenged index hamsters and naive hamsters into closed system units each comprising 2 different cages separated by a polyvinyl chloride air porous partition with unidirectional airflow within the isolator. The effect of a surgical mask partition placed between the cages was investigated. Besides clinical scoring, hamster specimens were tested for viral load, histopathology, and viral nucleocapsid antigen expression. Results Noncontact transmission was found in 66.7% (10/15) of exposed naive hamsters. Surgical mask partition for challenged index or naive hamsters significantly reduced transmission to 25% (6/24, P = .018). Surgical mask partition for challenged index hamsters significantly reduced transmission to only 16.7% (2/12, P = .019) of exposed naive hamsters. Unlike the severe manifestations of challenged hamsters, infected naive hamsters had lower clinical scores, milder histopathological changes, and lower viral nucleocapsid antigen expression in respiratory tract tissues. Conclusions SARS-CoV-2 could be transmitted by respiratory droplets or airborne droplet nuclei which could be reduced by surgical mask partition in the hamster model. This is the first in vivo experimental evidence to support the possible benefit of surgical mask in prevention of COVID-19 transmission, especially when masks were worn by infected individuals.

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Simulation of the Clinical and Pathological Manifestations of Coronavirus Disease 2019 (COVID-19) in a Golden Syrian Hamster Model: Implications for Disease Pathogenesis and Transmissibility

Clinical Infectious Diseases ◽

10.1093/cid/ciaa325 ◽

2020 ◽

Cited By ~ 166

Author(s):

Jasper Fuk-Woo Chan ◽

Anna Jinxia Zhang ◽

Shuofeng Yuan ◽

Vincent Kwok-Man Poon ◽

Chris Chung-Sing Chan ◽

...

Keyword(s):

Weight Loss ◽

Viral Load ◽

Syrian Hamster ◽

Clinical Signs ◽

Neutralizing Antibody ◽

Adaptive Mutation ◽

Lung Pathology ◽

Hamster Model ◽

Golden Syrian Hamster ◽

Virus Challenge

Abstract Background A physiological small-animal model that resembles COVID-19 with low mortality is lacking. Methods Molecular docking on the binding between angiotensin-converting enzyme 2 (ACE2) of common laboratory mammals and the receptor-binding domain of the surface spike protein of SARS-CoV-2 suggested that the golden Syrian hamster is an option. Virus challenge, contact transmission, and passive immunoprophylaxis studies were performed. Serial organ tissues and blood were harvested for histopathology, viral load and titer, chemokine/cytokine level, and neutralizing antibody titer. Results The Syrian hamster could be consistently infected by SARS-CoV-2. Maximal clinical signs of rapid breathing, weight loss, histopathological changes from the initial exudative phase of diffuse alveolar damage with extensive apoptosis to the later proliferative phase of tissue repair, airway and intestinal involvement with viral nucleocapsid protein expression, high lung viral load, and spleen and lymphoid atrophy associated with marked chemokine/cytokine activation were observed within the first week of virus challenge. The mean lung virus titer was between 105 and 107 TCID50/g. Challenged index hamsters consistently infected naive contact hamsters housed within the same cages, resulting in similar pathology but not weight loss. All infected hamsters recovered and developed mean serum neutralizing antibody titers ≥1:427 14 days postchallenge. Immunoprophylaxis with early convalescent serum achieved significant decrease in lung viral load but not in lung pathology. No consistent nonsynonymous adaptive mutation of the spike was found in viruses isolated from the infected hamsters. Conclusions Besides satisfying Koch’s postulates, this readily available hamster model is an important tool for studying transmission, pathogenesis, treatment, and vaccination against SARS-CoV-2.

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Cholesterol-Lowering Activity of Soy-Derived Glyceollins in the Golden Syrian Hamster Model

Journal of Agricultural and Food Chemistry ◽

10.1021/jf400557p ◽

2013 ◽

Vol 61 (24) ◽

pp. 5772-5782 ◽

Cited By ~ 15

Author(s):

Haiqiu Huang ◽

Zhuohong Xie ◽

Stephen M. Boue ◽

Deepak Bhatnagar ◽

Wallace Yokoyama ◽

...

Keyword(s):

Syrian Hamster ◽

Hamster Model ◽

Cholesterol Lowering ◽

Golden Syrian Hamster ◽

Lowering Activity

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Exposure route, sex, and age influence disease outcome in a golden Syrian hamster model of SARS-CoV-2 infection

10.1101/2021.06.12.448196 ◽

2021 ◽

Author(s):

Bryan D Griffin ◽

Bryce M Warner ◽

Mable Chan ◽

Emelissa J Mendoza ◽

Nikesh Tailor ◽

...

Keyword(s):

Respiratory Tract ◽

Syrian Hamster ◽

Lower Respiratory Tract ◽

High Titer ◽

Acute Infection ◽

High Volume ◽

Hamster Model ◽

Golden Syrian Hamster ◽

Low Volume ◽

Route Of Exposure

The emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resultant pandemic of coronavirus disease 2019 (COVID-19) has led to over one hundred million confirmed infections, greater than three million deaths, and severe economic and social disruption. Animal models of SARS-CoV-2 are critical tools for the pre-clinical evaluation of antivirals, vaccines, and candidate therapeutics currently under urgent development to curb COVID-19-associated morbidity and mortality. The golden (Syrian) hamster model of SARS-CoV-2 infection recapitulates key characteristics of severe COVID-19, including high-titer viral replication in the upper and lower respiratory tract and the development of pathogenic lesions in the lungs. In this work we examined the influence of the route of exposure, sex, and age on SARS-CoV-2 pathogenesis in golden hamsters. We report that delivery of SARS-CoV-2 primarily to the nasal passages (low-volume intranasal), the upper and lower respiratory tract (high-volume intranasal), or the digestive tract (intragastric) results in comparable viral titers in the lung tissue and similar levels of viral shedding during acute infection. However, low-volume intranasal exposure results in milder weight loss during acute infection while intragastric exposure leads to a diminished capacity to regain body weight following the period of acute illness. Further, we examined both sex and age differences in response to SARS-CoV-2 infection. Male hamsters, and to a greater extent older male hamsters, display an impaired capacity to recover from illness and a delay in viral clearance compared to females. Lastly, route of exposure, sex, and age were found to influence the nature of the host inflammatory cytokine response, but they had a minimal effect on both the quality and durability of the humoral immune response as well as the susceptibility of hamsters to SARS-CoV-2 re-infection. Together, these data indicate that the route of exposure, sex, and age have a meaningful impact SARS-CoV-2 pathogenesis in hamsters and that these variables should be considered when designing pre-clinical challenge studies.

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Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study

International Journal of Molecular Sciences ◽

10.3390/ijms22189935 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9935

Author(s):

Jesús Beltrán-García ◽

Juan J. Manclús ◽

Eva M. García-López ◽

Nieves Carbonell ◽

José Ferreres ◽

...

Keyword(s):

Septic Shock ◽

Outcome Prediction ◽

Fatal Outcome ◽

Neutrophil Extracellular Traps ◽

Endothelial Damage ◽

Rapid Progression ◽

Clinical Tool ◽

Sepsis Management ◽

Extracellular Traps ◽

Sepsis And Septic Shock

Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.

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Assessment of Macrophage Inflammatory Biomarkers and Neutrophil Extracellular Traps Associated Proteins in COVID-19 Patients

Blood ◽

10.1182/blood-2021-148166 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4193-4193

Author(s):

Laura Lopez de Frutos ◽

Irene Serrano-Gonzalo ◽

Barbara Menendez-Jandula ◽

Esther Franco-Garcia ◽

Carlos Lahoz ◽

...

Keyword(s):

Health System ◽

Macrophage Activation ◽

Conflicts Of Interest ◽

Clinical Manifestations ◽

Neutrophil Extracellular Traps ◽

Endothelial Damage ◽

Control Group ◽

P Value ◽

Extracellular Traps ◽

D Dimer

Abstract Background : The SARS-CoV-2 infection activates both innate and adaptive immune responses and induces an exaggerated cytokine storm leading to causes septic shock, acute respiratory distress syndrome, and/or multiple organ failure in critically ill patients. The knowledge of this dysregulated immune response is not well explained. One hypothesis is that the response of macrophages and neutrophils to infection is disproportionate, resulting in overproduction of cytokines and activation of neutrophils leading to the most severe complications of infection, including the production of multiple microthrombi and endothelial damage. Aim of the study: To evaluate the activation levels of macrophage biomarkers as well as indicators of the development of neutrophil extracellular traps (NET) in the first phase of infection in hospitalized patients with COVID19. Patients and Methods: We selected dry blood spot from a total of 60 previously identified SARS-CoV-2 infected subjects. Plasma samples were provided by the Aragon Health System Biobank's collection and were extracted within 5 days of symptom onset. Plasma from 60 healthy controls were used to stablish the control range for NETosis determination. The study was authorized by the Ethics Committee of the Aragon Health System and complies with the European General Data Protection Regulation (GDPR 2016/679) and LO 3/2018. Demographic characteristics, clinical manifestations, follow-up during hospitalization, associated comorbidities, and thrombotic complications were obtained from the database. Chitotriosidase activity (ChT), YKL40 chitinase and CCL18/PARC cytokine were measured as markers of macrophage activation. Myeloperoxidase (MPO), Neutrophil Elastase (NE), and S100A8/S100A9 Heterodimer (MPR) were immuno-quantified, levels of circulating free DNA (cfDNA) were measured as well as the presence of DNAsases by fluorimetry as indicators of Netosis. For the comparative analysis, we stratified patients by age groups and disease severity and used the Mann-Whitney U test for statistical comparison, considering a p-value < 0.05 as statistically significant. Results : A statistically significant increase in ChT (p=0.032) and CCL18/PARC (p=0.0001) was observed in the patients´ group. A comparative study with clinical variables and other inflammation markers as ferritin, D-dimer will be shown upon acceptance. Concerning NET markers, we found a statistically significant increase in MPO, NE, and MRP in COVID-19 patients (p=0.0001; p=0.0290; p=0.0001 respectively), as well as a statistically significant decrease in DNAsa (p=0.0001). No differences in cfDNA levels were observed. The table shows the median (quartile1-quartile3) for each marker in the control group and in the patient group. Conclusions : In this study, biomarkers of macrophage activation do not appear to be more sensitive than the indicators of inflammation in routine clinical practice (ferritin, D-dimer). Clinical cases of severe COVID-19 disease show an excessive NET formation, which contributes to vascular damage and the development of thrombosis. This work was supported by a research grant from FEETEG Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model

mBio ◽

10.1128/mbio.00974-21 ◽

2021 ◽

Author(s):

Santosh Dhakal ◽

Camilo A. Ruiz-Bedoya ◽

Ruifeng Zhou ◽

Patrick S. Creisher ◽

Jason S. Villano ◽

...

Keyword(s):

Sex Differences ◽

Severe Acute Respiratory Syndrome ◽

Clinical Isolate ◽

Syrian Hamster ◽

Antibody Responses ◽

Lung Imaging ◽

Hamster Model ◽

Golden Syrian Hamster ◽

Syrian Hamsters

Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human clinical isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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Golden Syrian hamster as a model to study cardiovascular complications associated with SARS-CoV-2 infection

eLife ◽

10.7554/elife.73522 ◽

2022 ◽

Vol 11 ◽

Author(s):

Zaigham Abbas Rizvi ◽

Rajdeep Dalal ◽

Srikanth Sadhu ◽

Akshay Binayke ◽

Jyotsna Dandotiya ◽

...

Keyword(s):

Syrian Hamster ◽

Troponin I ◽

Late Phase ◽

Cardiovascular Complications ◽

Therapeutic Interventions ◽

Wall Thickening ◽

Lung Pathology ◽

Hamster Model ◽

Golden Syrian Hamster ◽

Metabolic Marker

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in the Golden Syrian hamster causes lung pathology that resembles human coronavirus disease (COVID-19). However, extra-pulmonary pathologies associated with SARS-CoV-2 infection and post COVID sequelae remain to be understood. Here we show, using a hamster model, that the early phase of SARS-CoV-2 infection leads to an acute inflammatory response and lung pathologies, while the late phase of infection causes cardiovascular complications (CVC) characterized by ventricular wall thickening associated with increased ventricular mass/ body mass ratio and interstitial coronary fibrosis. Molecular profiling further substantiated our findings of CVC, as SARS-CoV-2-infected hamsters showed elevated levels of serum cardiac Troponin-I (cTnI), cholesterol, low-density lipoprotein and long-chain fatty acid triglycerides. Serum metabolomics profiling of SARS-CoV-2-infected hamsters identified N-acetylneuraminate, a functional metabolite found to be associated with CVC, as a metabolic marker was found to be common between SARS-CoV-2-infected hamsters and COVID-19 patients. Together, we propose hamsters as a suitable animal model to study post-COVID sequelae associated with CVC which could be extended to therapeutic interventions.

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