In early century, micro-organisms were considered as principal invaders which ruled host-pathogen interaction causing disease. In early 20th century, Smith recognized importance of host but continued to emphasize more microbial characteristics as primilarily responsible for microbial virulence . In his view, pathogenic microbes were having invading and defending functions that separated them from non-pathogenic microbes which lead to the type and conclusion of host-pathogen interaction . Zinsser, explained the term pathogenic which means capable of causing disease, he suggested that virulence had 2 attributes: (i) passive which possess microbial characteristics such as capsules that allows constancy in the host and (ii) Aggressive which includes toxins, etc. . Later, it was found that the outcome of interaction between host and pathogen is a diseased condition. This led to the origin of terms commensalism, mutualism, competition and parasitism. Commensalism refers to connection between two where one organism is benefited and other is neither benefited nor affected. On the other hand, relationship in which two dissimilar organisms are benefited is called mutualism. Competition refers to the interaction in which both the organisms are harmed and none is benefited. Whereas, symbiotic connection between two organisms out of which one known as parasite gets benefited at the cost of host is called parasitism. Koch's postulates which stated that: (i) There should be abundant micro-organisms in all organisms suffering from disease but none in unaffected animals. (ii) Micro-organisms should be isolated from diseased organism and should be grown in pure culture. (iii) The cultured organism should cause disease in healthy organism when transfected. (iv) The organism should be again isolated from inoculated, affected experimental host and recognized as identical to the original causative agent , were not fulfilled as they were describing behaviour of microbes and not general relationship between host and pathogen. Recently, microbiologists reviewed the concepts of virulence and pathogencity and conveyed that microbial pathogenesis reflects interaction between host and pathogen.
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The idea of model organism took place in middle of 19th century with the help of Charles Darwin and Gregor Mendel with their work on "Natural selection" and "Genetics of heredity" respectively. Model organisms are non-human species which are studied to gain better understanding of biological phenomena with the hope that discoveries made in the organism model will provide better insight into the workings of other organisms . Model organisms are classified as genetic models (e.g. Drosophila melanogaster, Caenorhabditis elegans, etc.), experimental models (e.g. Xenopus laevis, etc.) and genomic models (e.g. Puffer fish, etc.). Often, model organisms are chosen on the basis that they are amenable to experimental manipulation which usually includes characteristics such as short life cycle, genetic manipulation techniques, genome arrangement and traits such as size, generation time, accessibility, conservation of mechanisms and economic benefits. Multicellular non-mammalian hosts are used to study human diseases, to understand host-pathogen interactions, to examine physical barriers, to examine cellular mechanisms and molecular elements of the host response, to derive lots of genetic information to analyze development of humans and for study of gene structure and regulation. Host-pathogen interaction results in variety of responses like phagocytosis of pathogen, release of cytokines, secretion of toxins and production of reactive oxygen species. The disadvantages of using model organisms are genetic variance, background knowledge, transfer methodology and lack of methodology.
The table1 below shows non-mammalian model organisms which are used hosts (multicellular):
Provides awareness of cancer, brain diseases, behaviour, immunity, aging, multiple genes inheritance, and development.
To study cell differentiation and other developmental processes in intact organisms.
Useful in mutational and pathogenic studies due to presence of transparent egg embryonic developmental stage.
To study cell differentiation, signal transduction, cell sorting etc.
Useful in in-vivo toxicology and pathogenecity testing.
Table 1: Non-mammalian multicellular model organisms
Drosophila is commonly known as fruit fly of vinegar fly and belongs to family Drosophilidae. It is diphtheria which feeds and breeds on spoiled fruits. It exhibits sexual dimorphism. It is used as a model for infectious diseases in humans and is an important model for identifying novel genes and their products which can activates host defence mechanisms. It is the first organism used for genetic analysis. It is used for studying host pathogen interactions with Pseudomonas aeruginosa , M. marinum , Staphylococcus aureus  and L. monocytogenes . The salient features of its life cycle are a rapid period of embryogenesis followed by three periods of larval growth prior to metamorphosis as shown in fig1:
Always on Time
Marked to Standard
Fig1: Life cycle of Drosophila melanogaster [9,10]
Understanding host-pathogen interactions between Listeria monocytogenes and Drosophila melanogaster:
Listeria monocytogenes is an intracellular and facultative bacterial pathogen which has an ability to replicate within broad range of hosts. They were successful in causing lethal infections in adult fruit flies and their larvae with replication of bacteria before death of host. Bacteria were present in the cytosol of phagocytic cells of insect and were possessing ability of activating polymerization of host cell actin. For intracellular replication and cell-to-cell spreading within drosophila cells bacterial gene products were required. Moreover, for expression of L. monocytogenes virulence gene the temperature should be more than 30 degrees C. But bacteria within insect cells express virulence determinants at 25 degrees C. Mutant strains which were compromised for innate immunity showed more susceptibility to L. monocytogenes infection. This shows that infection of L. monocytogenes of fruit flies shows many features of mammalian infection which proves that Drosophila possess potential to serve as a genetically manageable host system which will assist the progress of analysis of cellular response of host against L. monocytogenes infection .
Advantages of using Drosophila melanogaster as a host model:
Overall cost is low as care and culture requires little space and less equipments.
It is easy to grow in laboratory as it is small.
Easy to identifty its morphology after they are anesthetized.
It has short generation time.
It has high reproducing capability.
Genetic mosaics permits analysis of lethal genes in adult flies.
Easy to create transgenic fruit flies which carries foreign DNA.
The first genome map was produced in Drosophila.
Facilitates genetic crossing as it's easy to distinguish males and females and isolate virgin females.
It has 3 autosomal chromosomes and one sex chromosome.
The mature larva shows giant chromosome called polytene in salivary glands of Drosophila which indicates zone of transcription and thus gene activity.
Its organ system is similar to mammals and so its physiology can be easily compared to mammals.
Disadvantages of using Drosophila melanogaster as a host model:
Generation time is longer than C. Elegans
Homologous recombination is not easy.
Does not show advanced immune system like zebra fish.
Danio rerio is commonly known as Zebrafish. It lives in fresh water and is found in South Asia and is a common aquarium fish. It is an important model organism to study vertebrate's development and disease, functioning of organs, behaviour and toxicology. Its shares certain features with humans such as blood, kidney and optical system. Its genome is fifty percent that of human and mouse genomes which helps in identification of important vertebrate genes. It is used for studying host-pathogen interaction with Pseudomonas aeruginosa , Streptococcus iniae  and Mycobacterium species . In life cycle of D. rerio cleavage does not involve yolk resulting into zygote on top of the yolk (fig.2).
Fig 2: Life cycle of Danio rerio 
Understanding host-pathogen interactions between Mycobacterium marinum and Danio rerio:
Danio rerio are exposed to various kinds of mycobacterial pathogens like Mycobacterium fortuitum, Mycobacterium abscessus and mycobacterium chelonae . M. Marinum is most exciting to study as it causes tuberculosis in fish. This pathogen has adverse effect on the host and possess tendency to infect all animals with same efficiency. One problem with M. Marinum infection is that fish can be infected for several weeks chronically without clear symptoms, before they fall ill and begin to shed bacilli. The interest in M. Marinum is due to its close relationship with M. tuberculosis and due to similarity of disease in fish to that of in humans, with its characteristic persistence and granuloma formation. M. marinum is capable to survive and undergo replication in adult Zebrafish which leads to an acute or chronic disease on the basis of inoculums used . Moreover, the oucome of disease is due to the type of strain causing disease. M. marinum strains can be divided into two clusters depending on genetic fingerprinting, and the cluster that possess most virulent strains also contains mycobacteria which are isolated from patients suffering from granulomas which is a skin infection caused by M. marinum . In Zebrafish embryo model, embryonic macrophages infected with M. marinum erupts and begins to amass which leads to activation of certain genes in M. marinum which are evoked only in enclosed environment of granuloma and not in isolated infected macrophages . This shows that granuloma formation occurs in absence of lymphocytes. Moreover, Zebrafish mutants can be used to analyze aggregation of macrophages . Zebrafish panther mutants are mutated in Zebrafish orthologue of the gene which encodes macrophage-colony stimulating factor-receptor. The mutant macrophages are not able to attack embryonic tissues but forms clumps when infected by M. marinum. This reveals that this activity is not dependent on M-CSF . Thus, this study reveals the molecular interactions which lead to granuloma formation and persistence of mycobacteria.
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Advantages of using Danio rerio as a host model:
It has short generation time.
Produce large number of embryos per mating.
Allows all stages of development to be observed as development of transparent embryos occurs outside the mother.
Zebrafish is used as a model in studying various human diseases and process of aging.
It has innate and immune system. It also has complement system like humans which activates by 3 different pathways: lectin, alternative and classical.
Genetic screening and real time visualization is possible.
They are easy to handle as they are small in size.
They are easy to cultivate and shows rapid embryonic development.
They express few counterparts of human Toll like receptors (TLR).
Disadvantages of using Danio rerio as a host model:
They lack cell markers and cell lines.
Gene duplication and phylogenetics make it difficult to identify correct orthologue or homologue counterpart.
They can be used to analyse bacterial infections in real time but they lose transparency after 5-6 days.
They have complex immune system.
They contain only sparsely arranged B and T cells.
G. mellonella is generally known as Greater wax moth or Honeycomb moth. Its larvae are effective to study host pathogen interactions. It is used for study host-pathogen interactions with Aspergillus fumigates , Yersinia pseudotuberculosis  and Cryptococcus neoformans . Y. Pseudotuberculosis is not harmful but it is pathogenic in immunocompromized individuals. The life cycle of G. mellonella consists of 5 stages namely egg, larva, spinning, pupa and adult.
Understanding host-pathogen interactions between Galleria mellonella and Cryptococcus neoformans:
Virulence of Cryptococcus neoformans in non-mammalian hosts suggests that C. neoformans is a non-specific pathogen. To study cryptococcal virulence, immune response of host to infection and effects of antifungal compounds, G. mellonella is killed by C. neoformans so that an invertebrate host model system is developed. After C. neoformans is injected into the insect hemocoel it proliferates and undergoes phagocytosis by host hemocytes and kills caterpillars at 37 as well as 30 degree C depending on cryptococcal strain and number of fungal cells injected. It was found that H99 strain of C. neoformans was the most virulent strain of all and kills caterpillars with low inocula. Even the genes of C. neoformans like CAP59, GPA1, RAS1 and PKA1 plays an important in killing the insect. Thus, G. mellonella- C. neoformans pathogenicity model can be a second-stringer for mammalian models of infection and may aid to study fungal virulence and efficacy of antifungal therapies in vivo [21, 22, and 23].
Advantages of using Galleria mellonella as a host model:
Since larva shows susceptibility to fungal infections and antifungal agents their roles can be easily studied.
It does not require specific requirements like microscopes, fly rooms, etc.
It can be cultivated at room temperature.
The larva exhibits systemic and local infection both.
It is available at very low cost.
Does not require laboratory expertise to inoculate it as its size is only 2.5 cm.
Disadvantages of using Galleria mellonella as a host model:
Complete sequenced genome is not available.
Due to its complexity it is very difficult to study response mechanism of this organism to different fungi.
D. discoideum grows as unicellular organisms but upon starvation they aggregate to form a multicellular tissue which is capable of differentiating into several cell types. During this developmental period it undergoes many cellular processes to form a spore-bearing fruiting body. This process includes chemotaxis, rearrangement of cytoskeleton, signal transduction, sorting of cell and formation of pattern. D. Discoideum provides insight into processes required for multicelluarity as its life cycle consists of both uni- and multi-cellular phases as shown in fig.3. It is used as a host model for several pathogens includingÂ Pseudomonas aeruginosa, Crytococcus neoformans, Mycobacterium spp. and Legionella pneumophila.
Fig.3: Life of Dictyostelium discoideum 
Understanding host-pathogen interaction between Dictyostelium discoideum and Legionella pneumophila:
L. pneumophila is an intracellular bacterial pathogen which is capable of replicating inside D. discoideum. Its ability to grow depends on growth state of cells. It follows same mechanism of growth in Dictyostelium as in amoebae and macrophages. This bacterium grows within membrane bound vesicles which are associated with rough endoplasmic reticulum. The dot/icm mutant of the bacteria which were blocked for growth in macrophages and amoebae did not develop even in D. discoideum. Internally, L. Pneumophila avoided degradation by D. discoideum and showed reduce fusion with endocytic compartments. During high level of infection, when D. discoideum grows as adherent monolayer it was found to be susceptible to bacterial infection and to cytotoxicity, whereas when it was grown in suspension it was resistant to cytotoxicity and thus did not show intracellular growth .
Advantages of using Dictyostelium discoideum as a host model:
It is easy to grow.
Used in biomedical studies.
Has a rapid doubling time.
Allows frequent harvesting for study.
Due to both uni- and multicellular life cycle it is an excellent model for developmental and cell biology studies.
Facilitates mutant selection due to its simplw life cycle.
Disadvantages of using Dictyostelium discoideum as a host model:
Glycosylation pattern varies.
Industrial production of protein is not achieved in D. discoideum and thus further optimizations are required in bioprocessing and fermentation.
C. elegans is commonly known as Roundworm. It is small, free living nematode found in soil. It is bacteriovorous as it feeds on bacteria like E.coli. It is diploid organism having two sex chromosomes and ten autosomal chromosomes. C. elegans is used to understand host pathogen interaction for gram positive bacteria like Staphylococcus aureus, Enterococcus and Gram negative bacteria like Salmonella typhimurium, Pseudomonas aeruginosa, serratia marcescenes and also a fungus Cryptococcus neoformans, etc. The short life cycle of C. elegans shown in fig.4 facilitates genetic experiments and is a major advantage for researchers working with this organism.
Fig.4: Life cycle of C. elegans 
Understanding host-pathogen interaction between Caenorhabditis elegans and Staphylococcus aureus:
S. aureus is a gram positive bacterium which is a leading cause of both community-acquired and hospital-acquired infections worldwide. It is an important cause of bovine and ovine mastitis [27, 28]. It causes infection both in humans as well as in C.elegans. It causes infection by accumulation of bacteria in digestive tract and finally kills the organism. Some virulence determinants like Quarum sensing global virulence regulatory system, global virulence regulator, V8 serine proteases, alpha hemolysin and alternative sigma factor. Some mutants of C. elegans were susceptible to infection caused by S. Aureus. Susceptibility of infection was enhanced in C. elegans when functional mutation of genes encoding p38 MAP pathway was lost. This proves that there are some host factors in C. elegans which alter susceptibility of gram positive pathogens .
Advantages of using Caenorhabditis elegans as a host model:
It is used to study cancer and aging.
Since it is transparent, it is easy to observe using fluorescent markers.
It is easy to maintain in laboratory.
Its cell lineage is well determined which makes it easier to study.
It has a fast and convenient life cycle.
Though it is a simple organism it shows the presence of a nervous system. Mechanisms like chemotaxis, thermotaxis can be studied.
Disadvantages of using Caenorhabditis elegans as a host model:
It size is very small which causes difficulty to biochemical amounts of nematodes at later stage.
Lack of knowledge concerning late-life pathology.
It lacks innate immunity.
It cannot survive at 37 degree C at which pathogens cause infection in humans.
Genetically they are not closely related to humans.
To conclude, there are many aspects of host-pathogen system that has been addressed by both experimental discoveries and computational models, though a comprehensive analysis of entire host-pathogen interaction including pathogen interference, host and pathogen response, etc. is a far-fetched goal. Current models focus mainly on host responses to infections or pathogenesity. Efforts are underway to combine both pathogen action and host response in a comprehensive, hybrid model, merging approaches with "omics" . Sophisticated experimental techniques such as protein expression, tags by quantum dots for localization and nano-biotechnological measurements on single cells promise new insights into complexity of host-pathogen systems. With respect to drug discovery, success stories of using model organisms are still anecdotal. In future, modelling predictions will most likely be only inputs in decision making process in pharmaceutical industries. A long-term goal for host-pathogen systems biology would include insilco models of an individual human fighting against pathogenic interactions.