Enterovirus A71 Induces Neurological Diseases and Dynamic Variants in Oral Infection of Human SCARB2-Transgenic Weaned Mice

2021 ◽  
Author(s):  
Jing-Yi Lin ◽  
Kuo-Feng Weng ◽  
Chih-Kuang Chang ◽  
Yu-Nong Gong ◽  
Guo-Jen Huang ◽  
...  
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Transgenic Mice ◽  
Public Health Problem ◽  
Viral Pathogenesis ◽  
Oral Route ◽  
Oral Infection ◽  
Viral Spread ◽  
Enterovirus A71 ◽  
Positive Strand Rna

Enterovirus A71 (EV-A71) and many members of the Picornaviridae family are neurotropic pathogens of global concern. These viruses are primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. An animal model of oral infection was developed using transgenic mice expressing human SCARB2 (hSCARB2 Tg), murine-adapted EV-A71/MP4 virus, and EV-A71/MP4 virus with an engineered nanoluciferase gene that allows imaging of viral replication and spread in infected mice. Next-generation sequencing of EV-A71 genomes in the tissues and organs of infected mice was also performed. Oral inoculation of EV-A71/MP4 or nanoluciferase-carrying MP4 virus stably induced neurological symptoms and death in infected 21-day-old weaned mice. In vivo bioluminescence imaging of infected mice and tissue immunostaining of viral antigens indicated that orally-inoculated virus can spread to the central nervous system and other tissues. Next-generating sequencing further identified diverse mutations in viral genomes that can potentially contribute to viral pathogenesis. This study presents an EV-A71 oral infection murine model that efficiently infects weaned mice and allows tracking of viral spread, features that can facilitate research into viral pathogenesis and neuroinvasion via the natural route of infection. Importance Enterovirus A71 (EV-A71), a positive-strand RNA virus of the Picornaviridae , poses a persistent global public health problem. EV-A71 is primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. We present an animal model of EV-A71 infection that enables the natural route of oral infection in weaned and non-immunocompromised 21-day-old hSCARB2 transgenic mice. Our results demonstrate that severe disease and death could be stably induced and viral invasion of the CNS could be replicated in this model, similar to severe real-world EV-A71 infections. We also developed a nanoluciferase-containing EV-A71 virus that can be used with this animal model to track viral spread after oral infection in real-time. Such a model offers several advantages over existing animal models, and can facilitate future research into viral spread, tissue tropism, and viral pathogenesis, all pressing issues that remain unaddressed for EV-A71 infections.

scholarly journals Animal Models for Influenza Research: Strengths and Weaknesses

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1011
Author(s):  
Thi-Quyen Nguyen ◽  
Rare Rollon ◽  
Young-Ki Choi
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Research Question ◽  
Viral Pathogenesis ◽  
Influenza Viruses ◽  
High Morbidity ◽  
Host Immune Responses ◽  
Transmission Mechanisms ◽  
Significant Public Health ◽  
Seasonal Epidemics

Influenza remains one of the most significant public health threats due to its ability to cause high morbidity and mortality worldwide. Although understanding of influenza viruses has greatly increased in recent years, shortcomings remain. Additionally, the continuous mutation of influenza viruses through genetic reassortment and selection of variants that escape host immune responses can render current influenza vaccines ineffective at controlling seasonal epidemics and potential pandemics. Thus, there is a knowledge gap in the understanding of influenza viruses and a corresponding need to develop novel universal vaccines and therapeutic treatments. Investigation of viral pathogenesis, transmission mechanisms, and efficacy of influenza vaccine candidates requires animal models that can recapitulate the disease. Furthermore, the choice of animal model for each research question is crucial in order for researchers to acquire a better knowledge of influenza viruses. Herein, we reviewed the advantages and limitations of each animal model—including mice, ferrets, guinea pigs, swine, felines, canines, and non-human primates—for elucidating influenza viral pathogenesis and transmission and for evaluating therapeutic agents and vaccine efficacy.

scholarly journals Establishment of a Poliovirus Oral Infection System in Human Poliovirus Receptor-Expressing Transgenic Mice That Are Deficient in Alpha/Beta Interferon Receptor

2007 ◽  
Vol 81 (15) ◽  
pp. 7902-7912 ◽  
Author(s):  
Seii Ohka ◽  
Hiroko Igarashi ◽  
Noriyo Nagata ◽  
Mai Sakai ◽  
Satoshi Koike ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transgenic Mice ◽  
Alimentary Tract ◽  
Oral Route ◽  
Oral Infection ◽  
Infection Model ◽  
Oral Infections ◽  
Beta Interferon ◽  
Interferon Receptor ◽  
Alpha Beta

ABSTRACT Poliovirus (PV) is easily transferred to humans orally; however, no rodent model for oral infections has been developed because of the alimentary tract's low sensitivity to the virus. Here we showed that PV is inactivated by the low pH of the gastric contents in mice. The addition of 3% NaHCO3 to the viral inoculum increased the titer of virus reaching the small intestine through the stomach after intragastric inoculation of PV. Transgenic mice (Tg) carrying the human PV receptor (hPVR/CD155) gene and lacking the alpha/beta interferon receptor (IFNAR) gene (hPVR-Tg/IfnarKO) were sensitive to the oral administration of PV with 3% NaHCO3, whereas hPVR-Tg expressing IFNAR were much less sensitive. The virus was detected in the epithelia of the small intestine and proliferated in the alimentary tract of hPVR-Tg/IfnarKO. By the ninth day after the administration of a virulent PV, the mice had died. These results suggest that IFNAR plays an important role in determining permissivity in the alimentary tract as well as the generation of virus-specific immune responses to PV via the oral route. Thus, hPVR-Tg/IfnarKO are considered to be the first oral infection model for PV, although levels of anti-PV antibodies were not elevated dramatically in serum and intestinal secretions of surviving mice when hPVR-Tg/IfnarKO were administered an attenuated PV.

scholarly journals Recent advances on animal models related to chronic obstructive pulmonary disease

2019 ◽  
Vol 02 (03) ◽  
pp. 93-104
Author(s):  
Shan Jiang ◽  
Nabjian Mohammadtursun ◽  
Jian Qiu ◽  
Qiuping Li ◽  
Jing Sun ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Animal Model ◽  
Animal Models ◽  
Pulmonary Disease ◽  
Economic Burden ◽  
Public Health Problem ◽  
Chronic Obstructive ◽  
Important Public Health Problem ◽  
Obstructive Pulmonary Disease ◽  
Short Period

Chronic obstructive pulmonary disease (COPD) has become an important public health problem in the world. According to reports, COPD ranks fourth in the global cause of death, causing a serious economic burden on society. The pathogenesis of COPD is complex, making it difficult to simulate the pathological changes and clinical features of COPD. Moreover, the COPD animal model has an irreplaceable role in the study of etiology, pathology and treatment. It is worth noting that the risk factors for chronic obstructive pulmonary disease persist, and the economic burden of global chronic obstructive pulmonary disease is expected to continue to increase in the coming decades. Establishing a standardized, a clinically realistic COPD animal model has always been a research direction that scholars are keen on. Therefore, it is essential to establish an economical animal model. The establishment of a suitable animal model can accurately simulate the pathological features of human chronic obstructive pulmonary disease and help to develop effective interventions and treatments in a short period of time. This review integrates the experimental animal species selected in the animal models used in COPD studies. Subsequently, different methods and mechanisms for establishing animal models were summarized according to different modeling factors. Finally, the criteria for evaluating existing animal models are discussed. It is hoped that the summary of this paper will guide the establishment of relevant animal models for future COPD research.

scholarly journals An oral inoculation infant rabbit model for Shigella infection

2019 ◽  
Author(s):  
Carole J. Kuehl ◽  
Jonathan D. D’Gama ◽  
Alyson R. Warr ◽  
Matthew K. Waldor
Keyword(s):  
Animal Models ◽  
Type Iii Secretion ◽  
Diarrheal Disease ◽  
Small Animal ◽  
Oral Route ◽  
Oral Infection ◽  
Secretion System ◽  
Colonic Epithelium ◽  
Intestinal Colonization ◽  
Small Animal Models

AbstractShigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. Following oral ingestion, the pathogen invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that oro-gastric inoculation of infant rabbits with S. flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell-to-cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro. Expression of the proinflammatory chemokine IL-8, detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.ImportanceShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that oro-gastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.

Inflammational Animal Models for Schizophrenia

2015 ◽  
Vol 223 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Georg Juckel
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Immune Activation ◽  
Microglial Activation ◽  
Treatment Options ◽  
Early Adulthood ◽  
Brain Regions ◽  
Synaptic Connections ◽  
Preventive Interventions ◽  
Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

scholarly journals Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4221
Author(s):  
Aage Kristian Olsen Alstrup ◽  
Svend Borup Jensen ◽  
Ole Lerberg Nielsen ◽  
Lars Jødal ◽  
Pia Afzelius
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Porcine Model ◽  
Animal Experiments ◽  
Radioactive Tracers ◽  
The Individual ◽  
Selection Of

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

Recent advances in animal model experimentation in autism research

2013 ◽  
Vol 26 (5) ◽  
pp. 264-271 ◽  
Author(s):  
Mousumi Tania ◽  
Md. Asaduzzaman Khan ◽  
Kun Xia
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Human Condition ◽  
Behavioral Alterations ◽  
Important Place ◽  
Adult Mice ◽  
Recent Advances ◽  
Model Study ◽  
Disease Biology ◽  
Animal Model Study

ObjectiveAutism, a lifelong neuro-developmental disorder is a uniquely human condition. Animal models are not the perfect tools for the full understanding of human development and behavior, but they can be an important place to start. This review focused on the recent updates of animal model research in autism.MethodsWe have reviewed the publications over the last three decades, which are related to animal model study in autism.ResultsAnimal models are important because they allow researchers to study the underlying neurobiology in a way that is not possible in humans. Improving the availability of better animal models will help the field to increase the development of medicines that can relieve disabling symptoms. Results from the therapeutic approaches are encouraging remarkably, since some behavioral alterations could be reversed even when treatment was performed on adult mice. Finding an animal model system with similar behavioral tendencies as humans is thus vital for understanding the brain mechanisms, supporting social motivation and attention, and the manner in which these mechanisms break down in autism. The ongoing studies should therefore increase the understanding of the biological alterations associated with autism as well as the development of knowledge-based treatments therapy for those struggling with autism.ConclusionIn this review, we have presented recent advances in research based on animal models of autism, raising hope for understanding the disease biology for potential therapeutic intervention to improve the quality of life of autism individuals.

scholarly journals Animal Models in Pharmacology: A Brief History Awarding the Nobel Prizes for Physiology or Medicine

Pharmacology ◽  
2021 ◽  
pp. 1-13
Author(s):  
Catarina V. Jota Baptista ◽  
Ana I. Faustino-Rocha ◽  
Paula A. Oliveira
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
20Th Century ◽  
Scientific Knowledge ◽  
Mode Of Action ◽  
Experimental Protocol ◽  
Domestic Species ◽  
Scientific Area ◽  
Different Types ◽  
Scientific Fields

<b><i>Background:</i></b> The Nobel Prize of Physiology or Medicine (NPPM) has recognized the work of 222 scientists from different nationalities, from 1901 until 2020. From the total, 186 award researchers used animal models in their projects, and 21 were attributed to scientists and projects directly related to Pharmacology. In the most recent years, genetics is a dominant scientific area, while at the beginning of the 20th century, most of the studies were more related to anatomy, cytology, and physiology. <b><i>Summary:</i></b> Mammalian models were used in 144 NPPM projects, being rodents the most used group of species. Moreover, 92 researchers included domestic species in their work. The criteria used to choose the species, the number of animals used and the experimental protocol is always debatable and dependent on the scientific area of the study; however, the 3R’s principle can be applied to most scientific fields. Independently of the species, the animal model can be classified in different types and criteria, depending on their ecology, genetics, and mode of action. <b><i>Key-Messages:</i></b> The use of animal models in NPPM awarded projects, namely in Pharmacology, illustrates their importance, need and benefit to improve scientific knowledge and create solutions. In the future, with the contribute of technology, it might be possible to refine the use of animal models in pharmacology studies.

scholarly journals Seasonal variation of hepatitis A virus infection in the city of Rio de Janeiro, Brazil

2002 ◽  
Vol 44 (5) ◽  
pp. 289-292 ◽  
Author(s):  
Livia Melo VILLAR ◽  
Vanessa Salete DE PAULA ◽  
Ana Maria Coimbra GASPAR
Keyword(s):  
Seasonal Variation ◽  
Rio De Janeiro ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Public Health Problem ◽  
Oral Route ◽  
Major Public Health Problem ◽  
Commercial Enzyme Immunoassay ◽  
National Reference Center ◽  
The City

Hepatitis A virus (HAV) infection constitutes a major public health problem in Brazil. The transmission of HAV is primarily by fecal-oral route so the water is an important vehicle of HAV dissemination. There is a great incidence of acute cases of hepatitis A in some areas of Brazil however the seasonal variation of these cases was not documented. The aim of this study was to determine the seasonality of HAV infection in Rio de Janeiro. From January 1999 to December 2001, 1731 blood samples were collected at the National Reference Center for Hepatitis Viruses in Brazil (NRCHV). These samples were tested by a commercial enzyme-immunoassay to detect anti-HAV IgM antibodies. Yearly positive rates were 33.74% in 1999, 32.19% in 2000, and 30.63% in 2001. A seasonal variation was recognized with the highest incidence in spring and summer. Furthermore a seasonal increase in incidence of HAV infection was found during the rainy season (December to March) because the index of rains is very high. It is concluded that HAV infections occur all year round with a peak during hot seasons with great number of rains.

scholarly journals NNK-Induced Lung Tumors: A Review of Animal Model

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Hua-Chuan Zheng ◽  
Yasuo Takano
Keyword(s):  
Lung Cancer ◽  
Animal Model ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Genetic Mutation ◽  
Lung Tumors ◽  
Chemotherapeutic Agents ◽  
Signal Pathways ◽  
Lung Carcinogenesis

The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models.

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