Hamster Strain Research Articles

Experimental evidence of the genetic hypothesis on the etiology of bicuspid aortic valve aortopathy in the hamster model

Bicuspid aortopathy occurs in approximately 50% of patients with bicuspid aortic valve (BAV), the most prevalent congenital cardiac malformation. Although different molecular players and etiological factors (genetic and hemodynamic) have been suggested to be involved in aortopathy predisposition and progression, clear etiophysiopathological mechanisms of disease are still missing. The isogenic (genetically uniform) hamster (T) strain shows 40% incidence of BAV, but aortic dilatations have not been detected in this model. We have performed comparative anatomical, histological and molecular analyses of the ascending aorta of animals with tricuspid aortic valve (TAV) and BAV from the T strain (TTAV and TBAV, respectively) and with TAV from a control strain (HTAV). Aortic diameter, smooth muscle apoptosis, elastic waviness, and Tgf-β and Fbn-2 expression were significantly increased in T strain animals, regardless of the valve morphology. Strain and aortic valve morphology did not affect Mmp-9 expression, whereas Mmp-2 transcripts were reduced in BAV animals. eNOS protein amount decreased in both TBAV and TTAV compared to HTAV animals. Thus, histomorphological and molecular alterations of the ascending aorta appear in a genetically uniform spontaneous hamster model irrespective of the aortic valve morphology. This is a direct experimental evidence supporting the genetic association between BAV and aortic dilatation. This model may represent a population of patients with predisposition to BAV aortopathy, in which increased expression of Tgf-β and Fbn-2 alters elastic lamellae structure and induces cell apoptosis mediated by eNOS. Patients either with TAV or BAV with the same genetic defect may show the same risk to develop bicuspid aortopathy.

Hypotension in hereditary cardiomyopathy.

It is well accepted that hypertension may lead to the development of heart failure (HF). However, little is known about the development of hypotension that may contribute to the onset of hereditary cardiomyopathy (HCM), thus promoting heart failure and early death. The purpose of this study is to verify whether a decrease in blood pressure takes place during different phases of HCM (asymptomatic, necrosis, hypertrophy, and heart failure). Using the well-known animal model, the UM-X7.1 hamster strain of HCM (HCMH), our results showed the absence of a change in mean arterial pressure (MAP) during the asymptomatic phase preceding the development of necrosis in HCMHs when compared to age-matched normal hamster (NH). However, there was a progressive decrease in MAP that reached its lowest level during the heart failure phase. The MAP during the development of the necrosis phase of HCM was accompanied by a significant increase in the level of the sodium-hydrogen exchanger, NHE1. Treatments with the potent NHE1 inhibitor, EMD 87580 (rimeporide), did not affect MAP of NH. However, treatments with EMD 87580 during the three phases of the development of HCM significantly reversed the hypotension associated with HCM.Our results showed that the development of HCM is associated with hypotension. These results suggest that a decrease in blood pressure could be a biomarker signal for HCM leading to HF and early death. Since the blockade of NHE1 significantly but partially prevented the reduction in MAP, this suggests that other mechanisms can contribute to the development of hypotension in HCM.

Roborovski hamster (Phodopus roborovskii) strain SH101 as a systemic infection model of SARS-CoV-2

ABSTRACT Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a Roborovski hamster strain SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. Roborovski hamster strain SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, labored breathing, dyspnea, cough, hunched posture, progressive weight loss, ruffled fur, and high fever following shaking chills. Histological examinations also revealed initial right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19.

Proteomic analysis of the ascending aorta in a hamster model of BAV disease

Bicuspid aortic valve (BAV) is the most prevalent human congenital cardiac malformation, which predisposes to ascending aortic dilatation (AD). Disease predisposition probably results from a congenital defect leading to anomalies in both, the morphology of the valve and the histology of the ascending aorta. Altered hemodynamics caused by the abnormal valve morphology would accelerate aortic media degeneration. AD in BAV patients results from medial smooth muscle cell (SMC) apoptosis probably caused by defective cell-matrix adhesion. Alterations of the TGFβ pathway seem to be central in disease initiation and progression, affecting extracellular matrix homeostasis. However, currently there are neither clear pathophysiological mechanisms nor effective biomarkers of disease predisposition or progression.The only spontaneous animal model of BAV disease consists of an inbred (T) strain of Syrian hamsters with a high (40%) incidence of BAV. Although AD has never been described in this model, animals of the T strain show significant SMC apoptosis and altered elastic lamina in the aortic media, irrespective of aortic valve morphology. We reasoned that analysing differentially expressed proteins in the aortic wall of animals with normal aortic valve (TAV) of the T strain compared to a control strain would inform about 1) the validity of the T strain as a model for BAV aortopathy predisposition; 2) the congenital origin of AD associated to BAV; 3) the proteins involved in AD etiology, independent of the effect of hemodynamics.To this aim, we compared the proteome of the ascending aorta of animals with TAV of the T strain (n=6) and a control outbred strain (n=6) by three independent experiments of quantitative proteomics (ESI-Quadrupole-Orbitrap LFQ). The analysis yielded expression data for over 1,954 proteins. Of these, 57 proteins (2.9%) showed concordant expression in at least two of the three experiments and were deregulated over 2.6-fold.Fourteen of these 57 proteins (24.6%) were previously proposed as AD biomarkers in patients. After database search, the 57 selected proteins were found to significantly interact (p<0.05 following FDR adjustment) within 16 molecular pathways and 27 biological processes on the STRING website. Most of these pathways and processes were relevant to AD pathophysiology, of note are the TGFβ non-canonical pathways (10/57; 17.5%; p=0.043), programmed cell death (14/57; 24.6%; p=3.5e-4), cell adhesion (15/57; 26.3%; p=2.4e-4), supramolecular fiber organization (9/57; 15.8%; p=3.8e-4) and stress fiber assembly (2/57; 3.5%; p=0.037).These results were obtained comparing the proteomes of aortas of individuals with TAV from an affected and a control strain. Thus, genetic rather than hemodynamic factors explain the structural abnormalities of the ascending aorta in this model. We propose that the T strain is an appropriate model for AD predisposition, as it replicates the ethiophysiological processes observed in patients. Deep study of our ascending aorta proteome analysis may uncover new molecular players and markers associated with aortopathy predisposition and progression.

In Vitro and In Vivo Models for Studying SARS-CoV-2, the Etiological Agent Responsible for COVID-19 Pandemic.

The emergence and rapid worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the scientific community to rapidly develop in vitro and in vivo models that could be applied in COVID-19 research. In vitro models include two-dimensional (2D) cultures of immortalized cell lines or primary cells and three-dimensional (3D) cultures derived from lung, alveoli, bronchi, and other organs. Although cell-based systems are economic and allow strict control of experimental variables, they do not always resemble physiological conditions. Thus, several in vivo models are being developed, including different strains of mice, hamsters, ferrets, dogs, cats, and non-human primates. In this review, we summarize the main models of SARS-CoV-2 infection developed so far and discuss their advantages, drawbacks and main uses.

&lt;i&gt;Phodopus roborovskii &lt;/i&gt;SH101 as a Systemic Infection Model of SARS-CoV-2

SARS-CoV-2 frequently causes systemic infection by breaking the bounds of the respiratory systems. Although the development of animal models recapitulating the clinical manifestations of systemic COVID-19 is of utmost importance to understand its pathogenesis, there has not been developed an animal model for systemic infection of SARS-CoV-2. Here we report that Phodopus roborovskii SH101, a laboratory inbred hamster strain of P. roborovskii, infected with SARS-CoV-2 breached the bounds of the respiratory system infection causing systemic infection as in the case of the human counterpart. P. roborovskii SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, dyspnea, cough, labored breathing, hunched posture, progressive weight loss, and ruffled fur, in addition to high fever accompanied by shaking chills. Histological examinations also revealed a serious right-predominated pneumonia as well as slight organ damages in the brain and liver as in the case of human systemic COVID-19 cases. Funding Statement: This research was supported by JINIS BDRD Research Institute of JINIS Biopharmaceuticals Inc. (Korea). Declaration of Interests: Authors declare no competing interests. Ethics Approval Statement: All procedures involving the mice and hamsters were accredited with the approval of the Institutional Animal Care and Use Committee (IACUC), in compliance with the guidelines of the Ethics Committee of Jeonbuk National University Laboratory Animal Center Guidelines on the Care and Use of Animals for Scientific Purposes. All animal experiments in this study were in accordance with the ARRIVE guidelines and checklist. All the animals used in this research were handled in a manner consistent with CDC/ABSA/WHO guidelines for the prevention of human infection with the SARS-CoV-2 virus.

Evaluation of an alternative method for production of biodiesel from processed fats derived from Category 1, 2 and 3 animal by-products (submitted by College Proteins).

An alternative method for the production of biodiesel from processed fats derived from Category 1, 2 and 3 animal by‐products was assessed. The method is based on a pre‐cleaning process, acidic esterification/transesterification of tallow using 1.5% methanesulfonic acid w/w; 140°C; 5.5 bar absolute pressure (bara); 4 h, followed by fractional distillation. The application focuses on the capacity of the alternative method to inactivate prions. Given the limitations that biodiesel presents for direct measurement of prion infectivity, the BIOHAZ Panel considered, based on the outcome of previous EFSA Opinions and current expert evaluation, that a reduction of 6 log10 in detectable PrPS c signal would be necessary to consider the process at least equivalent to previously approved methods for Category 1 animal by‐products. This is in addition to the inactivation achieved by the pressure sterilisation method applied before the application of any biodiesel production method. Experimental data were provided via ad hoc studies commissioned to quantify the reduction in detectable PrPS c in material spiked with scrapie hamster strain 263K, as measured by western blot, for the first two steps, with distillation assumed to provide at least an additional 3 log10 reduction, based on published data. Despite the intrinsic methodological caveats of the detection of PrPS c in laboratory studies, the BIOHAZ Panel considers that the alternative method, including the final fractional distillation, is capable of achieving the required 6 log10 reduction of the strain 263K PrPS c signal. Therefore, the method under assessment can be considered at least equivalent to the processing methods previously approved for the production of biodiesel from all categories of animal by‐product raw materials. It is recommended to check the feasibility of the proposed HACCP plan by recording the main processing parameters for a certain time period under real industrial conditions.

Bicuspid Aortic Valve in 2 Model Species and Review of the Literature.

Bicuspid aortic valve (BAV) is the most common human congenital cardiac malformation. Although the etiology is unknown for most patients, formation of the 2 main BAV anatomic types (A and B) has been shown to rely on distinct morphogenetic mechanisms. Animal models of BAV include 2 spontaneous hamster strains and 27 genetically modified mouse strains. To assess the value of these models for extrapolation to humans, we examined the aortic valve anatomy of 4340 hamsters and 1823 mice from 8 and 7 unmodified strains, respectively. In addition, we reviewed the literature describing BAV in nonhuman mammals. The incidences of BAV types A and B were 2.3% and 0.03% in control hamsters and 0% and 0.3% in control mice, respectively. Hamsters from the spontaneous model had BAV type A only, whereas mice from 2 of 27 genetically modified strains had BAV type A, 23 of 27 had BAV type B, and 2 of 27 had both BAV types. In both species, BAV incidence was dependent on genetic background. Unlike mice, hamsters had a wide spectrum of aortic valve morphologies. We showed interspecific differences in the occurrence of BAV between humans, hamsters, and mice that should be considered when studying aortic valve disease using animal models. Our results suggest that genetic modifiers play a significant role in both the morphology and incidence of BAV. We propose that mutations causing anomalies in specific cardiac morphogenetic processes or cell lineages may lead to BAV types A, B, or both, depending on additional genetic, environmental, and epigenetic factors.

Generation and characterization of an Il2rg knockout Syrian hamster model for XSCID and HAdV-C6 infection in immunocompromised patients.

ABSTRACTModel animals are indispensable for the study of human diseases, and in general, of complex biological processes. The Syrian hamster is an important model animal for infectious diseases, behavioral science and metabolic science, for which more experimental tools are becoming available. Here, we describe the generation and characterization of an interleukin-2 receptor subunit gamma (Il2rg) knockout (KO) Syrian hamster strain. In humans, mutations in IL2RG can result in a total failure of T and natural killer (NK) lymphocyte development and nonfunctional B lymphocytes (X-linked severe combined immunodeficiency; XSCID). Therefore, we sought to develop a non-murine model to study XSCID and the infectious diseases associated with IL2RG deficiency. We demonstrated that the Il2rg KO hamsters have a lymphoid compartment that is greatly reduced in size and diversity, and is impaired in function. As a result of the defective adaptive immune response, Il2rg KO hamsters developed a more severe human adenovirus infection and cleared virus less efficiently than immune competent wild-type hamsters. Because of this enhanced virus replication, Il2rg KO hamsters developed more severe adenovirus-induced liver pathology than wild-type hamsters. This novel hamster strain will provide researchers with a new tool to investigate human XSCID and its related infections.

LasDB: A collective database for laboratory animal strain resources.

BackgroundWith the aim of establishing the most comprehensive database of laboratory animal strains, the “laboratory animal strain resources database” (LasDB) was constructed as a searchable online database of all laboratory animal strains, stocks and mutant embryonic stem‐cell lines available worldwide, including inbred, outbred, mutant and genetically engineered strains.Methods MySQL database software was used to construct the LasDB, offering an easy‐to‐use interface.ResultsTo date, LasDB has a collection covering data for 21 596 mouse strains, 2062 rat strains, 13 monkey strains, 2 hamster strains, 5 dog strains, 5 rabbit strains and more than 50 other laboratory animal strains. LasDB will be continually improved with regular updates of new laboratory animal strains from all over the world.ConclusionTo the best of our knowledge, this is the first database that attempts to systematically integrate all available laboratory animal strain data with the aim of supporting open usage and full resource sharing.

Preserving prion strain identity upon replication of prions in vitro using recombinant prion protein

Last decade witnessed an enormous progress in generating authentic infectious prions or PrPSc in vitro using recombinant prion protein (rPrP). Previous work established that rPrP that lacks posttranslational modification is able to support replication of highly infectious PrPSc with assistance of cofactors of polyanionic nature and/or lipids. Unexpectedly, previous studies also revealed that seeding of rPrP by brain-derived PrPSc gave rise to new prion strains with new disease phenotypes documenting loss of a strain identity upon replication in rPrP substrate. Up to now, it remains unclear whether prion strain identity can be preserved upon replication in rPrP. The current study reports that faithful replication of hamster strain SSLOW could be achieved in vitro using rPrP as a substrate. We found that a mixture of phosphatidylethanolamine (PE) and synthetic nucleic acid polyA was sufficient for stable replication of hamster brain-derived SSLOW PrPSc in serial Protein Misfolding Cyclic Amplification (sPMCA) that uses hamster rPrP as a substrate. The disease phenotype generated in hamsters upon transmission of recombinant PrPSc produced in vitro was strikingly similar to the original SSLOW diseases phenotype with respect to the incubation time to disease, as well as clinical, neuropathological and biochemical features. Infrared microspectroscopy (IR-MSP) indicated that PrPSc produced in animals upon transmission of recombinant PrPSc is structurally similar if not identical to the original SSLOW PrPSc. The current study is the first to demonstrate that rPrP can support replication of brain-derived PrPSc while preserving its strain identity. In addition, the current work is the first to document that successful propagation of a hamster strain could be achieved in vitro using hamster rPrP.

Prion replication environment defines the fate of prion strain adaptation

The main risk of emergence of prion diseases in humans is associated with a cross-species transmission of prions of zoonotic origin. Prion transmission between species is regulated by a species barrier. Successful cross-species transmission is often accompanied by strain adaptation and result in stable changes of strain-specific disease phenotype. Amino acid sequences of host PrPC and donor PrPSc as well as strain-specific structure of PrPSc are believed to be the main factors that control species barrier and strain adaptation. Yet, despite our knowledge of the primary structures of mammalian prions, predicting the fate of prion strain adaptation is very difficult if possible at all. The current study asked the question whether changes in cofactor environment affect the fate of prions adaptation. To address this question, hamster strain 263K was propagated under normal or RNA-depleted conditions using serial Protein Misfolding Cyclic Amplification (PMCA) conducted first in mouse and then hamster substrates. We found that 263K propagated under normal conditions in mouse and then hamster substrates induced the disease phenotype similar to the original 263K. Surprisingly, 263K that propagated first in RNA-depleted mouse substrate and then normal hamster substrate produced a new disease phenotype upon serial transmission. Moreover, 263K that propagated in RNA-depleted mouse and then RNA-depleted hamster substrates failed to induce clinical diseases for three serial passages despite a gradual increase of PrPSc in animals. To summarize, depletion of RNA in prion replication reactions changed the rate of strain adaptation and the disease phenotype upon subsequent serial passaging of PMCA-derived materials in animals. The current studies suggest that replication environment plays an important role in determining the fate of prion strain adaptation.

Soluble polymorphic bank vole prion proteins induced by co-expression of quiescin sulfhydryl oxidase in E. coli and their aggregation behaviors

BackgroundThe infectious prion protein (PrPSc or prion) is derived from its cellular form (PrPC) through a conformational transition in animal and human prion diseases. Studies have shown that the interspecies conversion of PrPC to PrPSc is largely swayed by species barriers, which is mainly deciphered by the sequence and conformation of the proteins among species. However, the bank vole PrPC (BVPrP) is highly susceptible to PrPSc from different species. Transgenic mice expressing BVPrP with the polymorphic isoleucine (109I) but methionine (109M) at residue 109 spontaneously develop prion disease.ResultsTo explore the mechanism underlying the unique susceptibility and convertibility, we generated soluble BVPrP by co-expression of BVPrP with Quiescin sulfhydryl oxidase (QSOX) in Escherichia coli. Interestingly, rBVPrP-109M and rBVPrP-109I exhibited distinct seeded aggregation pathways and aggregate morphologies upon seeding of mouse recombinant PrP fibrils, as monitored by thioflavin T fluorescence and electron microscopy. Moreover, they displayed different aggregation behaviors induced by seeding of hamster and mouse prion strains under real-time quaking-induced conversion.ConclusionsOur results suggest that QSOX facilitates the formation of soluble prion protein and provide further evidence that the polymorphism at residue 109 of QSOX-induced BVPrP may be a determinant in mediating its distinct convertibility and susceptibility.

Identification of Reference Genes for Quantitative Real Time PCR Assays in Aortic Tissue of Syrian Hamsters with Bicuspid Aortic Valve

Bicuspid aortic valve (BAV) is the most frequent congenital cardiac malformation in humans, and appears frequently associated with dilatation of the ascending aorta. This association is likely the result of a common aetiology. Currently, a Syrian hamster strain with a relatively high (∼40%) incidence of BAV constitutes the only spontaneous animal model of BAV disease. The characterization of molecular alterations in the aorta of hamsters with BAV may serve to identify pathophysiological mechanisms and molecular markers of disease in humans. In this report, we evaluate the expression of ten candidate reference genes in aortic tissue of hamsters in order to identify housekeeping genes for normalization using quantitative real time PCR (RT-qPCR) assays. A total of 51 adult (180–240 days old) and 56 old (300–440 days old) animals were used. They belonged to a control strain of hamsters with normal, tricuspid aortic valve (TAV; n = 30), or to the affected strain of hamsters with TAV (n = 45) or BAV (n = 32). The expression stability of the candidate reference genes was determined by RT-qPCR using three statistical algorithms, GeNorm, NormFinder and Bestkeeper. The expression analyses showed that the most stable reference genes for the three algorithms employed were Cdkn1β, G3pdh and Polr2a. We propose the use of Cdkn1β, or both Cdkn1β and G3pdh as reference genes for mRNA expression analyses in Syrian hamster aorta.

16. STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus Type 5, Revealing an Important Role of Type I Interferon Response in Viral Control

Oncolytic vectors based on human species C adenovirus type 5 (Ad5) are being developed for cancer gene therapy. Studies on wild-type Ad5 in animal models are likely to provide important insights into the behavior of these vectors in patients. The most frequently used permissive immunocompetent animal model for Ad5 infection is the Syrian hamster. Ad5 (and Ad6) replicates in these animals and causes pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out (KO) by site-specific CRISPR/Cas9-mediated gene targeting. STAT2 is a critical element of the Type I and Type III interferon signal transduction pathways. STAT2 KO hamsters infected intravenously with Ad5 demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs (liver, lung, kidney) of STAT2 KO animals was 100- to 1000-fold higher than that in wild-type hamsters. We show that the Type I interferon pathway is disrupted in these hamsters, inasmuch as the interferon response genes PKR, OAS, and Mx2 were induced by Ad5 in the liver of wild-type but not STAT2 KO hamsters, revealing a critical role of interferon-stimulated genes in controlling Ad5 infection. Notably, the adaptive immune response to Ad5 is not adversely affected in STAT2 KO hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. In fact, anti-Ad5 neutralizing antibodies were 10-fold higher at 7 days postinfection in the STAT2 KO hamsters than in wild-type hamsters. T cell infiltration into the liver was similar at 3 and 7 days in the STAT2 KO and wild-type hamsters. Treatment of Ad5-infected STAT2 KO hamsters with high dose cyclophosphamide resulted in markedly increased mortality, pathogenesis, and virus replication in the liver (~1011 TCID50/g liver) at 10 days postinfection, likely because the adaptive immune response as well as other aspects of the innate response were abolished. This is the first study to report findings with a genetically modified Syrian hamster infected with human adenovirus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting Ad5 replication in a permissive animal model. This conclusion is in accord with a previous study in which we showed using a custom microarray platform that there is a robust up-regulation of genes involved in the innate immune response (e.g. OAS, PKR, IFN-inducible protein 10) in the liver at 18 h post-intravenous infection of wild-type Syrian hamsters with Ad5 (Ying, B. et al., Virology 485, 305, 2015). Besides providing an insight into adenovirus infection in humans, our results underscore the usefulness of Syrian hamsters as a permissive model for the study of species C human adenovirus and adenovirus-based vectors. In future studies, STAT2 KO hamsters bearing tumors could be used to explore the role of Type I and Type III interferon signaling on the efficacy of oncolytic adenovirus vectors.

The genetic audiogenic seizure hamster from Salamanca: The GASH:Sal.

The hamster has been previously described as a paroxysmal dystonia model, but our strain is currently recognized as a model of audiogenic seizures (AGS). The original first epileptic hamster appeared spontaneously at the University of Valladolid, where it was known as the GPG:Vall line, and was transferred to the University of Salamanca where a new strain was developed, named GASH:Sal. By testing auditory brainstem responses, the GASH:Sal exhibits elevated auditory thresholds that indicate a hearing impairment. Moreover, amplified fragment length polymorphism analysis distinguished genetic differences between the susceptible GASH:Sal hamster strain and the control Syrian hamsters. The GASH:Sal constitutes an experimental model of reflex epilepsy of audiogenic origin derived from an autosomal recessive disorder. Thus, the GASH:Sal exhibits generalized tonic-clonic seizures, characterized by a short latency period after auditory stimulation, followed by wild running, a convulsive phase, and finally stupor, with origin in the brainstem. The seizure profile of the GASH:Sal is similar to those exhibited by other models of inherited AGS susceptibility, which decreases after six months of age, but the proneness across generations is maintained. The GASH:Sal can be considered a reliable model of audiogenic seizures, suitable to investigate current antiepileptic pharmaceutical treatments as well as novel therapeutic drugs. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

A 1-bp deletion in Fgf5 causes male-dominant long hair in the Syrian hamster.

Hair length in mammals is generally regulated by the hair cycle, and its disruption leads to abnormal hair morphogenesis in several species. FGF5, one of the hair cycle regulators, has a role in inducing catagen, and that mutation causes abnormal hair length in both sexes in humans, mice, dogs, and cats. Male-dominant long-haired coat (MALC) is an inbred strain of Syrian hamster exhibiting spontaneous long hair in males. After castration, MALC exhibited significantly shorter hair than the control individuals, but testosterone administration to castrated MALC showed reversion to the original phenotype. Moreover, flutamide administration led to MALC phenotype repression. Histological analysis revealed that hair follicle regression was shown in the wild-type 4 weeks after depilation, but that of MALC remained in the anagen phase. We detected a c.546delG of Fgf5 in MALC (Fgf5malc) that might lead to truncation resulting from a frame shift in FGF5 (p.Arg184GlyfsX6). Additionally, homozygous Fgf5malc was only detected in long-haired (Slc:Syrian×MALC)F2 and (J-2-Nn×MALC)F2 progenies, and all homozygous wild and heterozygous Fgf5malc individuals showed normal hair length. Thus, Fgf5malc leads to male-dominant long hair via a prolonged anagen phase which is affected by testosterone in hamsters. To our knowledge, this report is the first to present the sexual dimorphism of hair length caused by the Fgf5 mutation.

STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.

The glycosylation status of PrPC is a key factor in determining transmissible spongiform encephalopathy transmission between species.

ABSTRACTThe risk of transmission of transmissible spongiform encephalopathies (TSE) between different species has been notoriously unpredictable because the mechanisms of transmission are not fully understood. A transmission barrier between species often prevents infection of a new host with a TSE agent. Nonetheless, some TSE agents are able to cross this barrier and infect new species, with devastating consequences. The host PrPC misfolds during disease pathogenesis and has a major role in controlling the transmission of agents between species, but sequence compatibility between host and agent PrPC does not fully explain host susceptibility. PrPC is posttranslationally modified by the addition of glycan moieties which have an important role in the infectious process. Here, we show in vivo that glycosylation of the host PrPC has a significant impact on the transmission of TSE between different host species. We infected mice carrying different glycosylated forms of PrPC with two human agents (sCJDMM2 and vCJD) and one hamster strain (263K). The absence of glycosylation at both or the first PrPC glycosylation site in the host results in almost complete resistance to disease. The absence of the second site of N-glycan has a dramatic effect on the barrier to transmission between host species, facilitating the transmission of sCJDMM2 to a host normally resistant to this agent. These results highlight glycosylation of PrPC as a key factor in determining the transmission efficiency of TSEs between different species.IMPORTANCE The risks of transmission of TSE between different species are difficult to predict due to a lack of knowledge over the mechanisms of disease transmission; some strains of TSE are able to cross a species barrier, while others do not. The host protein, PrPC, plays a major role in disease transmission. PrPC undergoes posttranslational glycosylation, and the addition of these glycans may play a role in disease transmission. We infected mice that express different forms of glycosylated PrPC with three different TSE agents. We demonstrate that changing the glycosylation status of the host can have profound effects on disease transmission, changing host susceptibility and incubation times. Our results show that PrPC glycosylation is a key factor in determining risks of TSE transmission between species.

Atypical and Classical Forms of the Disease-Associated State of the Prion Protein Exhibit Distinct Neuronal Tropism, Deposition Patterns, and Lesion Profiles

A number of disease-associated PrP forms characterized by abnormally short proteinase K-resistant fragments (atypical PrPres) were recently described in prion diseases. The relationship between atypical PrPres and PrP(Sc), and their role in etiology of prion diseases, remains unknown. We examined the relationship between PrP(Sc) and atypical PrPres, a form characterized by short C-terminal proteinase K-resistant fragments, in a prion strain of synthetic origin. We found that the two forms exhibit distinct neuronal tropism, deposition patterns, and degree of pathological lesions. Immunostaining of brain regions demonstrated a partial overlap in anatomic involvement of the two forms and revealed the sites of their selective deposition. The experiments on amplification in vitro suggested that distinct neuronal tropism is attributed to differences in replication requirements, such as preferences for different cellular cofactors and PrP(C) glycoforms. Remarkably, deposition of atypical PrPres alone was not associated with notable pathological lesions, suggesting that it was not neurotoxic, but yet transmissible. Unlike PrP(Sc), atypical PrPres did not show significant perineuronal, vascular, or perivascular immunoreactivity. However, both forms showed substantial synaptic immunoreactivity. Considering that atypical PrPres is not associated with substantial lesions, this result suggests that not all synaptic disease-related PrP states are neurotoxic. The current work provides important new insight into our understanding of the structure-pathogenicity relationships of transmissible PrP states.