**4. Host-pathogen interaction**

*Animal Models in Medicine and Biology*

vaccine available for HCV till date.

The term "cholera" was derived from Sanskrit meaning "stomach disturbance" [22]. Since, early 1800 century cholera outbreak turned out to be pandemic and caused millions to die, altogether six different pandemics took place the seventh started in the year 1961 and is still ongoing [23, 24]. In 2019 WHO report suggests 1.3 million to 4.0 million cases of cholera with an estimated 21,000–143,000 deaths worldwide [25].

Viral hepatitis is one of the most life threatening disease, it causes death to 1.4 million peoples across the globe reported in 2018 [26]. Globally around 260 million peoples are infected with HBV and 71 million with HCV infections are reported causing 90% of deaths among viral hepatitis patients [27]. The HBV and HCV has the highest prevalence rate in the global population at present, hepatitis viruses like HAV, HAD and HEV are endemic in many countries [26]. Currently there is no

The term Typhoid was coined from the Greek word "typhus" which means "Smoky" was used to relate the delirium symptom often associated with typhoid fever [28]. Typhoid fever is caused by gram-negative bacteria known as *Salmonella enterica serovar typhi*. Around 11–21 million cases of typhoid fever outbreak are reported annually, among that it causes death of 128,000–161,000 individuals worldwide [29].

Malaria fever is a severe parasitic disease caused by *Plasmodium falciparum* and *Plasmodium vivax transmits through* female *Anopheles gambiae* mosquitoes. In the year 2017 219 million cases were noted by World Health Organization, this seasonal

Viruses like herpes simplex virus HSV, HIV, mumps virus, measles virus and west Nile virus causes meningitis which causes frequent outbreaks in some regions [31]. Japanese encephalitis virus along with genus *Alphavirus* Togaviridae family viruses are arbovirus (arthropod borne virus) like California encephalitis, Chikungunya, dengue, Eastern equine encephalitis, Powassan, St. Louis encephalitis, Sindbis virus, West Nile, Yellow Fever and Zika virus are capable of causing encephalitis in humans [32, 33]. The viruses capable of causing hemorrhagic fever are dengue virus, rift valley virus, yellow virus, Crimean-Congo Hemorrhagic Fever, Lassa virus, Marburg virus and Ebola virus are epidemic diseases [34].

There are at present several bacterial, fungal and viral models of infection which were successfully demonstrated to infect flies and used it to understand drug efficacy. Drosophila model of infectious disease could be very low cost model

outbreak of malaria in 87 countries led to 435,000 deaths [30].

**3. Drosophila model to study highly infectious diseases**

**2.10 Viral meningitis, viral encephalitis and hemorrhagic fever viruses**

**2.6 Diarrhoeal disease**

*2.6.1 Cholera*

**2.7 Hepatitis**

**2.8 Typhoid**

**2.9 Malaria**

**110**

*Drosophila melanogaster* has a well-built immune system to withstand pathogenic incursion, comprising of cellular, humoral and innate immunity in an effective but in simpler form than humans [37]. However, due to evolutionarily conserved immune pathways found in vertebrates and invertebrates, several components of fly immune system are homologous to humans [38]. The immune activation in flies against pathogens involves processes like recognition, coagulation, melanisation, phagocytosis, apoptosis, regulation of iron metabolism, synthesis of antimicrobial peptides and production of reactive oxygen species [39].

The bacterial and fungal infection leads to the activation of dToll, Imd, Eiger (TNF family homolog) and insulin like receptors (FOXO) in *Drosophila*. The drosophila toll and Imd (immune deficiency) pathways function as innate immunity. Toll receptors in flies play an important part during viral, fungal and bacterial infection. The patterns recognition receptors (PRRs) initiate the signal in fly immune system depending on the type of pathogen upon interaction [40]. Gram positive and gram negative bacterial infection activates peptidoglycan recognition protein SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) respectively. PGRP-SA causes proteolytic cleavage of Spatzle upon stimulation of dToll, it mediates downstream signalling of dMyD88, Tube, Pelle, and DIF (dorsalrelated immunity factor) the NF-kB homolog. Imd an intracellular signalling protein located close to the transmembrane PGRP-LE and PGRP-LC proteins, activates Relish protein to trigger autophagy and phagocytosis through ImD regulated genes by rendering cellular immunity against gram negative bacteria [41]. Toll activates the nuclear factor DIF and it promotes humoral immunity in the fat body by producing varieties of anti-microbial peptides AMPs like attacin, cecropin, drosomycin, defensin, metchnikowin, diptericin and drosocin [42].

The fungal pathogen was found to be recognized by GNBP3 along with PGRPSA and GNBP1 it activates the drosophila toll receptors [43]. The Drosophila toll-5 (Tehao) and toll-9 plays major role during fungal infection by inducing Drosomycin gene [44].

During the preliminary stage of viral infection Drosophila toll receptor homolog of human TLR, Imd (TNF-alpha), Domeless (Jak–STAT), and RNAi plays a major role against viral infection these are components of innate immune system [45]. Similar to humans the viral glycoproteins are recognized by toll receptors like toll-4, while toll-7 dependent autophagy observed during viral infection in flies [42, 46]. Jak–STAT and Imd together mediates effective immunity against viral attack in flies [47]. The domeless-hop-stat2 pathway stimulated by upd1/2/3 activates Jak–STAT regulated genes responsible for controlling viral load; it is homologous to mammalian Jak–STAT pathway [48]. The Drosophila P53 and dP38 mediates apoptosis in

flies upon stress response generated due to DNA damage, P53 mediated apoptotic genes are regulated by Jak–STAT-MAPK [49]. The dP38 stimulation in flies triggers Unpraired gene (upd protein) a mammalian IL-6 homolog further activates Jak–STAT-*Turandots* pathway which increases tolerance towards the viral invasion [50]. The intrinsic to cell the Dicer2 a viral sensor protein mediates silencing through RNA-induced silencing complex (RISC) dependent RNAi production which inhibits viral components transcription and vago gene activation finally controls viral growth [51, 52]. The anti-viral RNAi are transported from one cell to another through canonical nano-tubes structures [53]. dERK pathway regulates viral infection of flies gut epithelial infection during orally challenge of arbovirus, Sindbis virus and vesicular stomatitis virus [54]. Despite of dynamic immune response against the viral infection viruses like Nora virus, Sigma virus (DmelSV), Drosophila C virus (DCV), and Drosophila X virus (DXV) can cause fatality in flies [55].
