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Experimental medicine is one of the necessary steps in drug design. When drugs are discovered its mechanism and activity should be tested before its commercialization. Humans are the ultimate models to check the drugs because of the uncertain validity and efficient targets. But conducting experiments in humans are methodologicaly and ethically wrong. This is the reason how model hosts are emerged. Model host is a simple species which is much studied due to its easiness in breeding and its similarity with higher organism that is extensively used in medical field to conduct experiments and study about diseases and its faster treatment. It can mimic the same diseases of complex organism so it is possible for the researcher to expect a same result as they do in humans. The basic fact is that many aspect of biology are same in most of the organisms. It is mainly used to find the host pathogen interaction in disease. For example Caenorhabditis elegans is the favorite model organism of scientists who works with humans. Gregor Mendel put forward the idea of model organism by conducting his genetics experiment in pea plants. Charles Darwin proved the theories of natural selection with different model organisms. Drosophila melanogaster became the favorite of biologist during early 1900. Most of the experiments conducted that period used drosophila as model. The real era of model hosts started when Frederick Banting discovered the cause of type 1 diabetes mellitus by removing the pancreas of a dog during 1921. He found that the lack of insulin produced from the pancreas results in diabetes. Model hosts are selected according to their ability to react on experimental manipulation. When a disease started spreading initially the biologists discover the gene associated with that disease. The next step is searching for such a gene in animal models. Then they study the function of that particular gene in the model organism and according to the result they select an organism. Certain criteria are used to choose the model organisms they are short lifecycle, small size, easy availability, easy to handle, gene manipulation and similarity with complex organisms. The selection of model hosts depends upon other unique attributes. It is selected according to the type of research carrying out. If it is developmental biology Danio rerio is the best model because it produces large, transparent embryos very fastly. A scientist doing research in behavioral genetics and neurobiology feels C elegans is the suitable model because the properties like simple nervous system and simple behavior are suitable for that research. The most widely used model organisms are Escherichia coli, Saccharomyces Cerevisiae (baker's yeast), Schizosaccharomyces pomb, Caenorhabditis elegans (Round worm), Drosophila melanogaster (Fruit fly), Danio rerio (Zebra fish), gallus domesticus (Frog), Mus musculus (mouse), Homo sapiens. Initially prokaryotes are commonly used as model organisms but the results were inaccurate and indefinite. This led to the usage of eukaryotic model hosts. The higher eukaryotic models are classified into mammalian, non-mammalian and plants. The major non-mammalian multicelular models are Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Galleria mellonella and Arabidopsis thaliana.
The nematodeC. elegans (round worm)is widely used as a host model for genetic studies. It possesses all the property of a good model host C. elegansis a free-living, non-parasitic organism which lives at an optimum temperature 20°C. It gives birth to approximately 300 progenies by self-fertilization. The worm is transparent so manipulation and observation is very easy. It feeds on bacteria such as E coli and it can be cheaply cultured in large numbers in laboratory. Its genome has been completely sequenced and mainly used in the studies of human leukemia and other infectious diseases. Biologists and geneticists are trying to solve the mystery of cell development and related biological problems, such as aging with the help of C elegans. The extensive genomic and genetic knowledge about C.elegans makes it easier to identify and characterize pathogens.
C elegans propagated by feeding E coli and survive for more than 3 weeks so this technique is used to infect it with pathogens. The worm is fed with pathogenic bacteria or fungi results in the infection of it with the same pathogen. For example Pseudomonas aeruginosa, a human pathogen kills C.elegans within three days. The P aeruginosa cells are found in the digestive tract of C.elegans. It depends on the P. aeruginosa strain and the medium on whichP. aeruginosais grown. The forward and genetic analysis is used to find out the genes involved in the killing of C. elegans. It was found that eight genes are involved in the pathogenesis which is similar to humans and other models. This information depicts the similarity between humans and C.elegans. C.elegans has become a host of many pathogens that affect humans like Serratia marcescens, Salmonella typhimurium, Staphylococcus aureus,Enterococcus faecalis, Yersinia, Streptococcus etc
C.elegans is very easy to grow and has rapid and convenient life cycle. The embryos are developed in 12 hours and it reaches its adult age within 2.5 days. It has a minimum life span of 14 days and maximum of 25 days. Rapid reproduction is another advantage. A single mature organism can give birth to 300 offspring at a time. Another advantage of C.elegans is it is transparent so it is very easy to manipulate and observe. Sometimes biologists can find out the results just by observation. C.elegans is smaller in size (97Mb). The adult worm is 1-1.5 mm in length and about 80 µm in width. So thousands of C.elegans can be grown in a Petri dish at a time. This can be used to culture large number of organism in limited space. Each adult worm contains 959 somatic cells of which 302 are neurons. The simple structure and arrangement of nervous system made it suitable model for neurobiology studies. It is very easy to carry out mutagenesis in C.elegans. This helps in the production of mutants which obtain defence against certain pathogenesis and helps in the treatment of many diseases or altered susceptibility to pathogen attack. . The availability of good amount of informations adds up advantage to this organism. Self fertilizing hermaphrodites are the peculiarity of C.elegans. The complete genome of C. elegans is sequenced which helps in the easy identification of genes and informations about genes. Moreover about 35% of C.elegans genes have homologs. "It has been estimated that about 42% of the human disease genes have an orthologue in the genome ofC. elegansincluding those associated with Alzheimer disease, hereditary non-polyposis colon cancer, spinal muscular atrophy, juvenile Parkinson's disease and many, many others.".
The disadvantages of C.elegans are it does not survive well at 37°C. Even if it has many similarities with humans it is not closely related to humans. So the assumptions and results of the experiments conducted in C.elegans may not be accurate. The small size can also be counted as a disadvantage because of the difficulty to get biochemical and pathological informations. "Further more immune system is quite different from complex mammalian immune system that is thereis no phagocytosis and are susceptible to the intra-pseudocoelomic presence of bacteria" They don't possess adaptive immunity and complementary pathways.
Drosophila is the most valuable and most studied organism in the biological research. It was one of the first organisms used in genetic analysis (1910). Thomas Hunt Morgan used drosophila for his famous heredity experiments. These are small flies with 2-2.5 mm length. Its life cycle is rapid and takes around 30 days in an optimum temperature of 28°C. Drosophila shows sexual dimorphism. The genome was almost completely sequenced and published. This organism also shows some close similarity with humans that is about 50% of the proteins coded by drosophila has human analogues. Drosophila possesses innate immunity response against pathogens but adaptive immunity is absent.
Drosophila melanogaster can be used as a model host for staphylococcus aureus infection. The concentrated inoculum of staphylococcus aureus is injected via the dorsal thorax of adult female flies so that the inoculum reaches the body cavity. Flies are then incubated at 30°C in culture vials. The flies were found to be dead due to the infection of the pathogen. Some flies took a maximum of 15 hours to die after the infection. The dead flies are collected and the gene expression was determined by analyzing the ß galactosidase activity and fluorescence is measured using fluorescence spectroscopy. The genes that involved in the action of pathogenesis identified. It was found that these genes show some resemblance to the human genes involved in the pathogenesis of S.aureus. Thus Drosophila melanogaster can be used as a model host for this s aureus interaction. The number of S.aureus cells needed for the infection and the strains that produce maximum pathogenicity can also be understood by host pathogenic interaction. The heat killed bacteria could not produce any infection which shows that the lethal infection can only be produced by live bacteria. It is also used to investigate pathogens infecting in mammals like Pseudomonas aeruginosa, Vibrio cholerae, Serratia marcescens, Zygomycetes infections.
The advantages of Drosophila includes it has a well defined genetics so it provides deeper understanding of molecular mechanisms in host pathogen interaction. The genomes are completely sequenced and genome mapping is extensively performed long before. As it is one of the first organisms used as model hosts the complete information is available. The genetic transformation technique is available since 1987. The small size easy to grow and rapid reproduction makes it as a favorite model for biologists. About 75% of the human diseases genes are closely associated with genes in Drosophila. It shares infections that are similar to human infections like intra cellular growth. Drosophila and humans show a good resemblance in stress response and aging so this fly can be used in the study of both aging and stress response.
Drosophila is not suited for embryological studies. The embryo development in drosophila is very complex. Due to small size of the organism the pathology and reason for death cannot be studied well. Again the optimum growth temperature is 28°C but the human pathogens grown in 37°C could not adapt this temperature. The ecology of drosophila is not well studied and well known so preserving the flies for experiment is a difficult process.
Danio rerio (zebrafish) is a freshwater fish which is widely used as aquarium fish all over the world. The work of George Streisingerat theUniversity of Oregonput forward the idea of zebra fish as a model organism It can produce almost 200 progenies per week from a single fish. Zebrafish is the vertebrate model organism. Due to it small size, rapid life cycle and transparent skin it is commonly used to conduct research on developmental biology. The embryo development and organ formation is clearly visible in the case of zebrafish so it is extensively used in the phenotypic analysis of embryogenesis and organogenesis.
The zebrafish possess a good immune system which shows close similarity to humans. Both innate and adaptive immune systems are active in zebrafish. Also it got a compliment system with all the three pathways. The zebra fish is commonly used as an infection model for pseudomonas aeruginosa. C.elegans and drosophila are widely used to study this infection but the poor immune system of this model hosts and resemblance between human and zebrafish's immune system made it easier to the scientists. When P aeruginosa is injected into the yolk circulation valley of the zebrafish embryo, it is found that the infection is based on the virulence of P aeruginosa 14 strain and the number of pathogen injected. Microinjection of more than 1700 P aeruginosa 14 bacterial cells resulted in the death of all embryos. This results shows a close resemblance with mammalian infection of PA14 and its optical transparency, ability to manipulate host immunity and ability to carry out both classical and chemical genetic studies made it more suitable models over existing models of P aeruginosa. It can be used as model hosts for Mycobacterium marinum,Salmonella Typhimurium,Vibrio anguillarum, Edwardsiell tarda,Staphylococcus aureus,andStreptococcus iniae
The advantages offered by zebrafish are as follows it is a vertebrate so it can act as a better model host for humans. The well developed immune system shows close resemblance with human immune system. Zebrafish is the simplest model host which shows close similarity with mammals. The optical transparency of embryos made it the favorite model host for developmental biologists, oncologists and toxicologists. The scientists can conduct a real time analysis of all experiments. Zebrafish shows a rapid reproduction and easy to handle. It can produce 200 embryos at a time and possess external fertilization which helps in experimental manipulations. "Zebrafish aregenetically tractable, both forward and reverse classical geneticapproaches are possible with this organism". It is also used to study enteropathogens and it has an easily categorized and conventional neurons. The genomes of zebra fish are sequenced and mapping is also carried out. "The genes can be silenced with antisence morpholino oligonucleotides.
The main disadvantage of zebrafish is its complex genome. The genome is difficult to analyse so a little knowledge about its genetics comparing to other model hosts. Zebrafish is relatively a new model host so little knowledge about its ecology and life. The optimum temperature of zebrafish is 28°C but most of the mammalian pathogens infect in body temperature (37°C) so it affects the experiment outcome. The real time analysis of zebrafish embryo can only be observed 5-6 days because it lost its transparency due to the production of pigments. Lack of call markers and cell lines in the immune system make it inappropriate to model many infections. Finally it is phylogenetically distant from humans.
Galleria mollonella is the larvae of greater wax moth which is used to study the host pathogen interaction in entomopathogenic microbes. It is grayish brown in colour and grows upto a length of 3 cm. The larva is simple in structure and easy to handle. It is inexpensive and do not require feeding. Usually it feeds on honey comb. Rapid reproduction is another characteristic of Galleria. It lay around 500-1000 eggs at a time and the eggs may hatch within 5 days. Cellular and humoral response to disease is present on Galleria. So it is widely used as model organism for pathogenicity and toxicology.
Galleria mollonella extensively used to study the host pathogen interaction with Acinetobacter baumannii, a gram negative bacteria. Acinetobacter baumannii is one of the major infectious pathogen that causes many diseases. Acinetobacter baumannii
Colonies with pHC60 plasmid is constructed by mixing it with E coli at different laboratory condition. The galleria larvae are collected and injected with the inoculums of different strains. The injected larvae is incubated in plastic containers. The dead larvae are counted for 6 days starting from the day of injection. "Survival curves were plottedusing the Kaplan-Meier method, and differences in survival werecalculated by using the log-rank test" . The killed cells are observed and analysed different factors. The GFP tagged hemocytes are observed using microscopes and the level of infection and the mechanism is analysed. It was found that as a first defense mechanism hemocytes are released to phagocyte the pathogens. The infection on Galleria varies according to the strain of Acinetobacter baumannii injected. Temperature also plays an important role in the infection of pathogen because Galleria grows in an optimum temperature of 37°C. Finally and most importantly the genes involved in infection has close resemblance with humans which shows the ability of Galleria to act as a good model host for pathogen infection.
The major advantage of Galleria over other model organism is its growth temperature. Gallerias optimum temperature (37°C) is adaptable for human pathogens. Another advantage is to access antibiotic efficiency against various bacterial and funagal pathogens. The production of hemocytes during pathogen infection makes Galleria a unique model organism. It gives some resistance to the model towards the invading pathogens. When compared to other model hosts Galleria got convenient injection feasibility. Well developed immune response with innate immunity, hemolymph formation and cellular phagocytosis. Recognition of other microbes with the help of receptors is present in Galleria. Rapid reproduction, small size and easy handling are added advantages
The life span of Galleria mollonella is long compared to other models. The caterpillar is only a small stage in the life cycle of Galleria so preserving in lab is not possible. After 10 days of larvae formation it enters into the next stage of life cycle. The genomes and genetics of Galleria is not well studied. Phylogenetically not closely related to mammals.
Arabidopsis thaliana is a dicoteledonous plant commonly used as a model organism for plant pathogenic infection. It is a member of Brassicaceae (cabbage) family. Friedrich Laibach firstly proposed Arabidopsis as a model organism in 1943. One of the main characteristic this plant is the presence of smallest genome in plant kingdom (115,409,949 base pairs of DNA distributed in 5 chromosomes). It is widely known as mouse-ear cress. The life span of Arabidopsis is almost six weeks. It is a small plant and needs only less space to grow (It can grow in Petri plates under optimum conditions). A single plant can produce thousands of progenies. Arabidopsis posses first plant genome that sequenced and completed. It completed 4 years ahead of schedule (2000). Large numbers of mutant populations are available.
The host pathogen interaction in Arabidopsis thaliana can be described by the infection of plant pathogen Botrytis cinerea. Botrytis cinerea is a fungal pathogen that infects a wide range of the plants. Gray mold is a common diseases caused by this pathogen. To study the genes and mechanism behind the infection it is infected in the host Arabidopsis thaliana. 5µl spore suspension of Botrytis cinerea is inoculated into a leaf of Arabidopsis thaliana. The leaf has been punctured before inoculation. Within one day of inoculation the leaf forms some necrotic lesions on its surface and after 1 week Arabidopsis has been completely infected by the host pathogen. The leaves are analyzed by RNA analysis and microscopic analysis methods. It was found that Arabidopsis possess some defense mechanism against the invasion of pathogens in the plant. The gene that involved in infection and susceptibility of Arabidopsis has been identified. The gene has got many orthologs when compared with tobacco plant. This shows that host pathogen interaction in Arabidopsis and other plants are similar. The infection depends on the amount of inoculants added and the strain of Botrytis cinerea inoculated. Host pathogen interaction of Pseudomonas aeruginosa, Enterococco sfaecalis and Staphylococcus aureus has been studied in Arabidopsis thalaiana.
The advantages are smallest plant genome so can easily manipulated and studied. More knowledge about genome results in more host pathogen interaction. Short lifecycle and produces large number of progenies. Powerful reverse and forward genetics. Mutagenesis can be done easily in this plant so large amount of mutant populations are available. Most of the mutants are well charecterised. This gives the biologist a number of choices during their experiment. Transformation technology of Arabidopsis is very simple and elegant so experiments are conducted very easily. Most of the genes in Arabidopsis have analogs in other plants.
The functions of almost 50% of the proteins of Arabidopsis are unknown. These badly affect the interaction experiments. It lacks some important biological processes in other plants which has got application in agriculture and human health. Due to the presence of small genome the number of repetitive DNA may be less. So it cannot completely represent the higher plants. Genetic variance is another disadvantage especially for plant models. The biochemistry of this plant is not well known and no possibility of homologous recombination.
The host pathogen interaction advantage and disadvantage of five different non-mammalian multi cellular hosts are discussed. Caenorhabditis elegans, Drosophila melanogaster, galleria mollonella, Danio rerio and Arabidopsis thaliana are the models that described here. The selection of models for a particular host pathogen interaction experiment depends upon its genetics and resemblance with mammals. Eventhough these models shows some resemblance with humans it is a fact that the host pathogen interaction may not always give accurate results. This is because of the phylogenetic distance of these organisms with mammals. Due to the technological advancement future of model organism will be humanised models.
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