丙型肝炎病毒感染实验动物模型的研究进展

丙型肝炎病毒（HCV）感染是导致人类慢性病毒性肝炎、肝硬化和肝癌的最主要病因之一。由于缺乏合适的HCV感染实验动物模型,使得针对HCV感染更为有效的疗法及疫苗的研发滞后。黑猩猩是HCV感染研究的最佳实验动物,但由于其来源有限、价格昂贵及临床症状等诸多问题,其应用受限,因此发展新的实验动物模型用于HCV感染相关的基础和应用研究迫在眉睫。近年来,以啮齿类等动物为替代模型取得了不少进展,应用转基因等实验技术使替代动物感染了HCV,并成功应用于多个学科领域的研究。本文分析了HCV自然感染的实验动物、自然感染和非自然感染的替代实验动物在致病机制研究、药物评价和疫苗研发应用中的优缺点及未来研究趋势。     

Influenza virus infections and immunity: a review of human and animal models.

Studies of the pathogenesis of influenza infection have involved the extensive use of animal models. The development of the current concepts of immunity to influenza and of the contribution the secretory immune system makes toward the protection of mucosal surfaces against influenza infection would have been impossible without this use of animals. The pathology and clinical signs of influenza infection in both natural and experimental hosts, the advantages and disadvantages of the most common experimental influenza infection models, and the contribution of animal models to the understanding of local and systemic immunity to influenza infection are discussed.     

Mice,microbes and models of infection

We urgently need animal models to study infectious disease. Mice are susceptible to a similar range of microbial infections as humans. Marked differences between inbred strains of mice in their response to pathogen infection can be exploited to analyse the genetic basis of infections. In addition, the genetic tools that are available in the laboratory mouse, and new techniques to monitor the expression of bacterial genes in vivo, make it the principal experimental animal model for studying mechanisms of infection and immunity.     

Animal models for gastric Helicobacter immunology and vaccine studies

Over the last decade animal models have been used extensively to investigate disease processes and therapy for Helicobacter pylori infections. The H. pylori animal models which have been used in pathogenesis and vaccine studies include the gnotobiotic pig, non-human primates, cats, dogs, and several species of rodents including mice, rats, gerbils and guinea pigs. H. felis infection of mice and H. mustelae infection of ferrets have also been used. Recently, investigators have begun using transgenic mice and gene-targeted 'knock-out' mice to investigate Helicobacter infections. Each of these animal models has distinct advantages and disadvantages which are discussed in this minireview. The choice of an animal model is dictated by factors such as cost and an understanding of how each model will or will not allow fulfillment of experimental objectives.     

Rats, mice and men - models for immune effector mechanisms against schistosomiasis

Experimental studies have demonstrated the diversity of immune effector mechanisms against schistosomes. Among the various animal models, the rat appears as an excellent experimental system for investigation of antibody-mediated immunity to Schistosoma mansoni. Rat monoclonal antibodies have allowed the identification of effector and regulatory mechanisms operating in human infection, together with the characterization of protective antigens, leading to promising approaches to vaccine development.     

体液免疫抗白念珠菌感染的研究

探讨抗白念珠菌IgY及其免疫血清对多种动物模型感染白念珠菌的保护作用。制备烧伤继发感染白念珠菌大鼠、白念珠菌性阴道炎小鼠及免疫功能低下小鼠多种动物感染模型 ,分别应用抗白念珠菌IgY、鼠免疫血清和生理盐水对照 ,观察比较各自的作用。抗白念珠菌IgY对烧伤继发感染白念珠菌大鼠及白念珠菌性阴道炎小鼠均有明显的保护作用 ;鼠免疫血清则对阻止远程靶器官的白念珠菌扩散有较好的作用。体液免疫成份抗白念珠菌IgY及其免疫血清对烧伤继发感染白念珠菌大鼠、白念珠菌性阴道炎小鼠及免疫功能低下小鼠均有良好的保护作用。     

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.     

Plant models for animal pathogenesis

Several bacteria that are pathogenic to animals also infect plants. Mechanistic studies have proven that some human/animal pathogenic bacteria employ a similar subset of virulence determinants to elicit disease in animals, invertebrates and plants. Therefore, the results of plant infection studies are relevant to animal pathogenesis. This discovery has resulted in the development of convenient, cost-effective, and reliable plant infection models to study the molecular basis of infection by animal pathogens. Plant infection models provide a number of advantages in the study of animal pathogenesis. Using a plant model, mutations in animal pathogenic bacteria can easily be screened for putative virulence factors, a process which if done using existing animal infection models would be time-consuming and tedious. High-throughput screening of plants also provides the potential for unravelling the mechanisms by which plants resist animal pathogenic bacteria, and provides a means to discover novel therapeutic agents such as antibiotics and anti-infective compounds. In this review, we describe the developing technique of using plants as a model system to study Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus pathogenesis, and discuss ways to use this new technology against disease warfare and other types of bioterrorism.     

The benefits of using diverse animal models for studying pertussis

Pertussis, a respiratory disease caused by infection with Bordetella pertussis, represents one of the most devastating diseases in infants and young children worldwide. Significant research efforts over the last five decades have led to the introduction of two types of vaccines, which are now available worldwide and which have significantly reduced the global incidence of pertussis. The use of animal models and, in particular, the mouse model has benefited in the development of these vaccines tremendously. However, open questions regarding the duration of immunity, the type of immune response needed for protection and the role of mucosal and innate immunity in disease protection still remain. Here, we review the various animal models available currently and their benefits for studying this important disease.     

Intestinal strongyloidiasis and hyperinfection syndrome

In spite of recent advances with experiments on animal models, strongyloidiasis, an infection caused by the nematode parasite Strongyloides stercoralis, has still been an elusive disease. Though endemic in some developing countries, strongyloidiasis still poses a threat to the developed world. Due to the peculiar but characteristic features of autoinfection, hyperinfection syndrome involving only pulmonary and gastrointestinal systems, and disseminated infection with involvement of other organs, strongyloidiasis needs special attention by the physician, especially one serving patients in areas endemic for strongyloidiasis. Strongyloidiasis can occur without any symptoms, or as a potentially fatal hyperinfection or disseminated infection. Th₂ cell-mediated immunity, humoral immunity and mucosal immunity have been shown to have protective effects against this parasitic infection especially in animal models. Any factors that suppress these mechanisms (such as intercurrent immune suppression or glucocorticoid therapy) could potentially trigger hyperinfection or disseminated infection which could be fatal. Even with the recent advances in laboratory tests, strongyloidiasis is still difficult to diagnose. But once diagnosed, the disease can be treated effectively with antihelminthic drugs like Ivermectin. This review article summarizes a case of strongyloidiasis and various aspects of strongyloidiasis, with emphasis on epidemiology, life cycle of Strongyloides stercoralis, clinical manifestations of the disease, corticosteroids and strongyloidiasis, diagnostic aspects of the disease, various host defense pathways against strongyloidiasis, and available treatment options.     

痔疮动物模型制作方法研究进展

近年来,在兔、大鼠、小鼠和犬等动物种属成功地建立了巴豆油、醋酸、感染与创伤诱导的痔疮动物模型,每种动物模型各有优缺点,应用合理的动物模型能更好地开展痔的实验和临床研究。随着治痔药物的深入研究,动物模型有很好发展和应用,本文综述了痔疮动物模型制作方法研究进展。     

Animal models for the study of immunity in human filariasis

A major challenge to the development of vaccines against human lymphatic filariasis and onchocerciasis is to direct the immune response toward elimination of the early, prepathogenic larval stages and away from responses that mediate pathology. In this review, James Lok and David Abraham discuss the various animal models that have been used to investigate the pathways leading to immunity, immunological tolerance and chronic pathology in these diseases. Owing to the strict host specificities of the human-dwelling filariae, no single model serves to duplicate exactly all these aspects. Nevertheless, it has been possible to demonstrate a protective immune response invoked by and directed against incoming third-stage larvae of both lymphatic and skin-dwelling filariae. The fact that subsets of the sequelae of human filarial infection can be duplicated in animal systems should also aid in unravelling the mechanisms determining the course of infection and in ensuring that vaccine candidates do not produce an inappropriate immunopathological response. A proposed scheme for using animal models in screening candidates for a vaccine against Onchocerca volvulus is presented.     

A model for the dynamics of human lymphatic filariasis

In this paper, Bryan Gren fell, Edwin Michael and David Denham review the appropriateness of feline filariasis as a model of the population dynamics of human lymphatic filarial infection and disease. Because of the longevity of infection and our inability to measure the adult parasite population in humans, research in filariasis is particularly dependent on the use of laboratory animal models. We demonstrate that Brugia pahangi infection patterns in the cat closely parallel those of Brugia and Wuchereria in humans. Although primary infections in 'susceptible' cats are long-lived, repeatedly infected animals show evidence of concomitant immunity which prevents the establishment of later cohorts of infective larvae. Furthermore, there is some evidence from macro filarial length distributions of 'stunting' of adult worms during long-term repeat infections. Cats can also show an 'acute' response that spontaneously eliminates infections, and this appears to be due to a combination of intrinsic and dynamic mechanisms. As in humans, pathology in cat filariasis develops as a sequel to the asymptomatic microfilaremic state, largely as a result of re-expression of immunity. The relationship between macro filarial burdens and microfilariae in blood is positive but portrays a high degree of variability. The cat model provides an important tool for elucidating the relationships between infection, immunity and disease dynamics in lymphatic filariasis, and we conclude by suggesting directions for further work in this area.     

The cotton rat model of respiratory viral infections

Development of successful vaccines against human infectious diseases depends on using appropriate animal models for testing vaccine efficacy and safety. For some viral infections the task is further complicated by the frequently changing genetic make-up of the virus, as in the case of influenza, or by the existence of the little-understood phenomenon of vaccine-enhanced disease, as in the case of respiratory syncytial virus (RSV). The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of the RSV vaccine-enhanced disease. Recently, using cotton rats, we have demonstrated that vaccination against another paramyxovirus, human metapneumovirus (hMPV), can also lead to vaccine-enhanced disease. In addition to the study of paramyxoviruses, S. hispidus presents important advantages for the study of orthomyxoviruses such as influenza. The cotton rat is susceptible to infection with unadapted human influenza strains, and heterosubtypic immunity to influenza can be evoked in S. hispidus. The mechanisms of influenza, RSV, and hMPV pathogenesis and immunity can now be investigated in the cotton rat with the development of species-specific reagents for this animal model.     

Patterns in parasite epidemiology: the peak shift

A characteristic relationship between infection and host age, with levels of infection reaching a peak in particular age classes, has been reported for many parasites. However, several field studies have shown that this relationship is not invariant: if age-infection data are compared across host populations, the peak level of infection is higher and occurs at a younger age when the transmission rate is high, and is lower and occurs at an older age when it is low. This pattern is called the ;peak shift'. Here, Mark Woolhouse reviews the evidence for and the implications of the peak shift. The peak shift is consistent with the predictions of mathematical models that assume gradually acquired protective immunity, and this interpretation is supported by experimental studies using animals. This agreement between theory, experimental evidence and field studies strongly suggests that acquired immunity has a major impact on epidemiological patterns not only for parasites such as malaria, where the importance of acquired immunity is not in doubt, but also for many parasitic helminths, where the role of acquired immunity is less widely accepted.     

Modeling motivational deficits in mouse models of schizophrenia: behavior analysis as a guide for neuroscience

In recent years it has become possible to develop animal models of psychiatric disease in genetically modified mice. While great strides have been made in the development of genetic and neurobiological tools with which to model psychiatric disease, elucidation of neural and molecular mechanisms thought to underlie behavioral phenotypes has been hindered by an inadequate analysis of behavior. This is unfortunate given the fact that the experimental analysis of behavior has created powerful methods for isolating and describing the functional properties of behavioral mechanisms that are capable of providing deep understanding of behavioral phenotypes. A better understanding of the biological basis of normal behavior and its disturbance in psychiatric disease will require the application of these rigorous behavior analytic tools to animal models. In this review we provide an example of a merging of genetic and behavioral methods and illustrate its utility in the analysis of a mouse model of the motivational deficits in schizophrenia. The synergy between basic behavior analysis, neuroscience, and animal models of psychiatric disease has great potential for achieving a deeper understanding of behavior and its neurobiological mechanisms as well as for leading to improvements in diagnosis and treatment in clinical settings.     

Mosquito immune responses and malaria transmission: lessons from insect model systems and implications for vertebrate innate immunity and vaccine development

The introduction of novel biochemical, genetic, molecular and cell biology tools to the study of insect immunity has generated an information explosion in recent years. Due to the biodiversity of insects, complementary model systems have been developed. The conceptual framework built based on these systems is used to discuss our current understanding of mosquito immune responses and their implications for malaria transmission. The areas of insect and vertebrate innate immunity are merging as new information confirms the remarkable extent of the evolutionary conservation, at a molecular level, in the signaling pathways mediating these responses in such distant species. Our current understanding of the molecular language that allows the vertebrate innate immune system to identify parasites, such as malaria, and direct the acquired immune system to mount a protective immune response is very limited. Insect vectors of parasitic diseases, such as mosquitoes, could represent excellent models to understand the molecular responses of epithelial cells to parasite invasion. This information could broaden our understanding of vertebrate responses to parasitic infection and could have extensive implications for anti-malarial vaccine development.     

Defining the protective antibody response for HIV-1

The development of an effective HIV-1 vaccine would be greatly facilitated by knowledge regarding the type and quantity of antibodies that are protective. Since definitive immune correlates are established only after a vaccine has been shown to be effective in humans, animal models are often used to guide vaccine development. Experimental lentivirus infection of non-human primates has shown that neutralizing antibodies can protect against infection. Most specifically, studies of passive antibody transfer in the chimeric SIV/HIV-1 immunodeficiency virus (SHIV) model have provided quantitative data on the level of protective antibody required. While direct extrapolation to humans is difficult, these data likely provide important insights into the protection afforded by antibodies against HIV-1. When used alone, high levels of neutralizing antibodies are required to completely block infection. However, even modest levels of antibody can provide partial protection and affect disease course. Understanding the exact level of protective antibody becomes even more complex in the setting of active immunization and coexisting cellular immunity. Despite this uncertainty, recent findings from lentiviral animal models strongly suggest that neutralizing antibodies will contribute to protection against HIV-1. Based on these data, a major goal of HIV-1 vaccine strategies is the induction of neutralizing antibodies against circulating primary HIV-1 strains.     

Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): A model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans

ABSTRACT: BACKGROUND: Hepatitis B virus (HBV) infection continues to be an escalating global health problem. Feasible and effective animal models for HBV infection are the prerequisite for developing novel therapies for this disease. The tree shrew (Tupaia) is a small animal species evolutionary closely related to humans, and thus is permissive to certain human viral pathogens. Whether tree shrews could be chronically infected with HBV in vivo has been controversial for decades. Most published research has been reported on adult tree shrews, and only small numbers of HBV infected newborn tree shrews had been observed over short time periods. We investigated susceptibility of newborn tree shrews to experimental HBV infection as well as viral clearance over a protracted time period. RESULTS: Forty-six newborn tree shrews were inoculated with the sera from HBV-infected patients or tree shrews. Serum and liver samples of the inoculated animals were periodically collected and analyzed using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Southern blot, and immunohistochemistry. Six tree shrews were confirmed and four were suspected as chronically HBV-infected for more than 48 (up to 228) weeks after inoculation, including three that had been inoculated with serum from a confirmed HBV-infected tree shrew. CONCLUSIONS: Outbred neonatal tree shrews can be long-term chronically infected with HBV at a frequency comparable to humans. The model resembles human disease where also a smaller proportion of infected individuals develop chronic HBV related disease. This model might enable genetic and immunologic investigations which would allow determination of underlying molecular causes favoring susceptibility for chronic HBV infection and disease establishment vs. viral clearance.     

Tet system的调控原理及其在转基因小鼠模型上的应用

基因表达的调控是分子生物学研究的一个重要问题,也是基因治疗和基因功能研究的重要手段。诱导性基因表达系统可以从时间上调控基因的表达,是基因治疗和基因功能研究的重要工具之一。其中,四环素诱导基因表达系统(tetracycline inducible expression system,Tet system)是应用最广泛的一种,它可以在时间和空间上对基因进行严谨和高效地诱导表达。基于该系统获得了不同用途的转基因动物,这些模型动物的建立为研究特定基因的功能及其在疾病发生中的作用打下了实验基础。现就四环素诱导表达系统的原理和在小鼠模型上的研究应用做一综述。