Towards a small animal model for hepatitis C.
Ontology highlight
ABSTRACT:
SUBMITTER: Ploss A
PROVIDER: S-EPMC2775186 | biostudies-other | 2009 Nov
REPOSITORIES: biostudies-other
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Project description:Background & aimsHEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV (Rocahepevirus ratti; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection.MethodsIn this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored.ResultsA high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats (p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection.ConclusionsWe developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients.Lay summaryConvenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans.
| S-EPMC9424580 | biostudies-literature
Project description:Hepaciviruses in a small animal infection model
| PRJEB48702 | ENA
Project description:BackgroundIn human medicine, questions regarding heritable disorders are dealt with by clinical geneticists and genetic counselors and both the field, their roles and the tools they use are well-defined. Even though the prevalence of diseases is far higher and scientific literature agrees on expectations towards an increased importance, this does not seem to be the case in veterinary medicine. While we hypothesize that there will be an overlap, some characteristics uniquely linked to veterinary medicine might not be covered.MethodsTo investigate this in-depth and in an attempt to define the field, we compared the internationally accepted definitions and its subparts on genetic counseling in human medicine with what is found in veterinary literature and what was seen in cats and dogs presented at our dedicated small animals clinical genetics/genetic counseling clinic. The results were used in a stepwise analysis that lead to a set of three potential definitions (i.e. on what genetic counseling is, who provides it and which tools are used) that fullfill four criteria (i.e. definitions have to be clear/self-explanatory, minimally sufficient, complete and valid).ResultsThe short version of the definition of genetic counseling in veterinary medicine is: "Genetic counseling is the process of helping animal owners and breeders understand - and adapt to - the medical, psychological, familial implications of genetic contributions to disease." Genetic counseling in small animal practice is currently provided by veterinarians and the tools that are used, can be divided in five categories. The signalment of the patients revealed that both cats (30%) and dogs (70%) and various breeds, the two sexes (37% males, 63% females) and all age categories (puppy/kitten-senior) were represented. Furthermore, 73% of the patients were referred by or needed to be referred to other disciplines.ConclusionThese definitions are derived from human and veterinary literature, and an evaluation based on patient data has demonstrated that these definitions meet all the criteria of a correct definition (i.e. clear, minimally sufficient, complete and valid). With these definitions and case descriptions, our aim is to contribute to the formal foundation of genetic counseling in veterinary medicine.
| S-EPMC11846242 | biostudies-literature
Project description:Many people worldwide suffer from hepatitis C virus (HCV) infection, which is frequently persistent. The lack of efficient vaccines against HCV and the unavailability of or limited compliance with existing antiviral therapies is problematic for health care systems worldwide. Improved small animal models would support further hepacivirus research, including development of vaccines and novel antivirals. The recent discovery of several mammalian hepaciviruses may facilitate such research. In this study, we demonstrated that bank voles (Clethrionomys glareolus) were susceptible to bank vole-associated Hepacivirus F and Hepacivirus J strains, based on the detection of hepaciviral RNA in 52 of 55 experimentally inoculated voles. In contrast, interferon α/β receptor deficient C57/Bl6 mice were resistant to infection with both bank vole hepaciviruses (BvHVs). The highest viral genome loads in infected voles were detected in the liver, and viral RNA was visualized by in situ hybridization in hepatocytes, confirming a marked hepatotropism. Furthermore, liver lesions in infected voles resembled those of HCV infection in humans. In conclusion, infection with both BvHVs in their natural hosts shares striking similarities to HCV infection in humans and may represent promising small animal models for this important human disease.
| S-EPMC8708279 | biostudies-literature
Project description:APOBEC3 are cytidine deaminases that convert cytidine to uridine residues. APOBEC3A and APOBEC3B enzymes able to target genomic DNA are involved in oncogenesis of a sizeable proportion of human cancers. While the APOBEC3 locus is conserved in mammals, it encodes from 1-7 genes. APOBEC3A is conserved in most mammals, although absent in pigs, cats and throughout Rodentia whereas APOBEC3B is restricted to the Primate order. Here we show that the rabbit APOBEC3 locus encodes two genes of which APOBEC3A enzyme is strictly orthologous to human APOBEC3A. The rabbit enzyme is expressed in the nucleus and the cytoplasm, it can deaminate cytidine, 5-methcytidine residues, nuclear DNA and induce double-strand DNA breaks. The rabbit APOBEC3A enzyme is negatively regulated by the rabbit TRIB3 pseudokinase protein which is guardian of genome integrity, just like its human counterpart. This indicates that the APOBEC3A/TRIB3 pair is conserved over approximately 100 million years. The rabbit APOBEC3A gene is widely expressed in rabbit tissues, unlike human APOBEC3A. These data demonstrate that rabbit could be used as a small animal model for studying APOBEC3 driven oncogenesis.
| S-EPMC6021247 | biostudies-literature
Project description:METHODS::An orthotopic non-small cell lung cancer model in NMRI-nude mice was established to investigate the complementary information acquired from 80 kVp microcone-beam CT (micro-CBCT) and bioluminescence imaging (BLI) using different angles and filter settings. Different micro-CBCT-based radiation-delivery plans were evaluated based on their dose-volume histogram metrics of tumor and organs at risk to select the optimal treatment plan. RESULTS::H1299 cell suspensions injected directly into the lung render exponentially growing single tumor nodules whose CBCT-based volume quantification strongly correlated with BLI-integrated intensity. Parallel-opposed single angle beam plans through a single lung are preferred for smaller tumors, whereas for larger tumors, plans that spread the radiation dose across healthy tissues are favored. CONCLUSIONS::Closely mimicking a clinical setting for lung cancer with highly advanced preclinical radiation treatment planning is possible in mice developing orthotopic lung tumors. ADVANCES IN KNOWLEDGE::BLI and CBCT imaging of orthotopic lung tumors provide complementary information in a temporal manner. The optimal radiotherapy plan is tumor volume-dependent.
| S-EPMC6541189 | biostudies-literature
Project description:Gene expression profiling by RNAseq of lung, thymus, heart, pancreas, kidney, spleen and liver tissues from woodchuck as a preclinical animal model for chronic hepatitis B
2019-09-25 | GSE137911 | GEO
Project description:BackgroundThe identification of hepatitis E virus (HEV) from rabbits motivated us to assess the possibility of using rabbits as a non-human primate animal model for HEV infection and vaccine evaluation.Methodology/principal findingsFirst, 75 rabbits were inoculated with seven strains of genotypes 1, 3, 4, and rabbit HEV, to determine the appropriate strain, administrative route and viral dosage. Second, 15 rabbits were randomly divided into three groups and vaccinated with 0 µg (placebo), 10 µg and 20 µg of HEV candidate vaccine, HEV p179, respectively. After three doses of the vaccination, the rabbits were challenged with 3.3×10(5) genome equivalents of genotype 4 HEV strain H4-NJ703. The strain of genotype 1 HEV was not found to be infectious for rabbits. However, approximately 80% of the animals were infected by two rabbit HEV strains. All rabbits inoculated with a genotype 3 strain were seroconverted but did not show viremia or fecal viral shedding. Although two genotype 4 strains, H4-NJ153 and H4-NJ112, only resulted in part of rabbits infected, another strain of genotype 4, H4-NJ703, had an infection rate of 100% (five out of five) when administrated intravenously. However, only two out of fifteen rabbits showed virus excretion and seroconversion when inoculated orally with H4-NJ703 of three different dosages. In the vaccine evaluation study, rabbits vaccinated with 20 µg of the HEV p179 produced anti-HEV with titers of 1?10(4)-1?10(5) and were completely protected from infection. Rabbits vaccinated with 10 µg produced anti-HEV with titers of 1?10(3)-1?10(4) and were protected from hepatitis, but two out of the five rabbits showed virus shedding.Conclusions/significanceRabbits may be served as an alternative to the non-human primate models for HEV infection and vaccine evaluation when certain virus strains, appropriate viral dosages, and the intravenous route of inoculation are selected.
| S-EPMC3521758 | biostudies-literature
Project description:With the cost/yield-ratio of drug development becoming increasingly unfavourable, recent work has explored machine learning to accelerate early stages of the development process. Given the current success of deep generative models across domains, we here investigated their application to the property-based proposal of new small molecules for drug development. Specifically, we trained a latent diffusion model-DrugDiff-paired with predictor guidance to generate novel compounds with a variety of desired molecular properties. The architecture was designed to be highly flexible and easily adaptable to future scenarios. Our experiments showed successful generation of unique, diverse and novel small molecules with targeted properties. The code is available at https://github.com/MarieOestreich/DrugDiff . SCIENTIFIC CONTRIBUTION: This work expands the use of generative modelling in the field of drug development from previously introduced models for proteins and RNA to the here presented application to small molecules. With small molecules making up the majority of drugs, but simultaneously being difficult to model due to their elaborate chemical rules, this work tackles a new level of difficulty in comparison to sequence-based molecule generation as is the case for proteins and RNA. Additionally, the demonstrated framework is highly flexible, allowing easy addition or removal of considered molecular properties without the need to retrain the model, making it highly adaptable to diverse research settings and it shows compelling performance for a wide variety of targeted molecular properties.
| S-EPMC11854002 | biostudies-literature
Project description:The development of shark single domain antibodies (sdAbs) is hindered by the high cost and tediousness of large-sized shark farming. Here, we demonstrated white-spotted bamboo sharks (Chiloscyllium plagiosum) being cultivated commercially as a promising small animal model to produce sdAbs. We found that immunoglobulin new antigen receptor (IgNAR) presented in bamboo shark genome, transcriptome, and plasma. Four complete IgNAR clusters including variable domains (vNARs) were discovered in the germline, and the Variable-Joining pair from IgNAR1 cluster was dominant from immune repertoires in blood. Bamboo sharks developed effective immune responses upon green fluorescent protein (GFP), near-infrared fluorescent protein iRFP713, and Freund's adjuvant immunization revealed by elevated lymphocyte counts and antigen specific IgNAR. Before and after immunization, the complementarity determining region 3 (CDR3) of IgNAR were the major determinant of IgNAR diversity revealed by 400-bp deep sequencing. To prove that bamboo sharks could produce high-affinity IgNAR, we isolated anti-GFP and anti-iRFP713 vNARs with up to 0.3 and 3.8 nM affinities, respectively, from immunized sharks. Moreover, we constructed biparatopic vNARs with the highest known affinities (20.7 pM) to GFP and validated the functions of anti-GFP vNARs as intrabodies in mammalian cells. Taken together, our study will accelerate the discovery and development of bamboo shark sdAbs for biomedical industry at low cost and easy operation.
| S-EPMC8692893 | biostudies-literature