Introduction:Background:The title of this research is Protein-protein interaction networks (PPIN). Protein-protein interactionnetworks (PPIN) is the mathematical representation of physical interactionbetween proteins in the cell. These contacts are specific (www.ebi.ac.uk).It isalso essential in drug development, since drugs can affect PPIs.Dengue fever iscaused by Aedes aegypti mosquitoes which are the principle vector in thetransmission of disease.
Mosquito Aedes aegypti transmits diseases like dengue,chikungunya and yellow fever and feeds almost exclusively on humans(http://www.oxitec.com/life-cycle-of-aedes-aegypti/).The aim of this research topic is to study Dengue:Denguecreates a main public health problem in tropical and sub-tropical countries 1.
Presently Dengue virus threatens half of the world’spopulation and is a significant public health problem in many tropical regionsof the world 10. Genetic diversity of dengue virus suggests its origin inAsia according to geographic distribution 7. Current estimates show at least 390 million dengueinfections occurs annually, of which approximately100 million are symptomatic 1. The infection is caused by dengue virus (DENV)member of the Flaviviridae family that co-circulates in nature as four diverseantigenic serotypes (DENV1 – 4) Dengue virus (DEN-1, DEN-2, DEN-3, and DEN-4) caused dengueinfection in human body. These four viruses are different interaction withantibody that’s why called serotypes.
The four dengue viruses are 65% genomes are similar but there is slight geneticvariation in single serotype (/www.nature.com/scitable/topicpage/dengue-viruses) .Flaviviruses aresmall, enveloped viruses with a single-stranded positive-sense RNA, which canbe translated into a single polyprotein by host cell proteins. The polyproteinis then cleaved into distinct proteins by both viral and host proteases 4.
The dengue constitute three structural protein capsid, pre-membrane andenvelope (10).DENV infection in humans is generally asymptomatic,but symptomatic cases can diverge from a minor and self-limited fever to apotentially fatal hemorrhagic syndrome 1. Denguevirus (DENV) is the causative agent of dengue hemorrhagic fever and dengue shocksyndrome. The human population globallyaffecting potentially by these disease 1. Approximately 390 million peopleacquire DENV infection through mosquito bites each year, and 96 million of thempresent varying degrees of clinical manifestations 1.
However, the underlying mechanisms of these severe dengue diseases remain unclearand neither a dengue vaccine nor a specific antiviral drug is commerciallyavailable 3.Epidemiology: In 1943 first time RenKimura and Susumu Hotta isolated the dengue virus.These two scientist werestudying blood samples of patients taken during the epidemic in Nagasaki japan.
A year later, Albert B. Sabin and Walter Schlesinger independently isolated thedengue virus(www.nature.
com/scitable/).Infections caused by thefour serotypes of dengue viruses borneby the Aedes mosquito can result in dengue fever (DF), denguehemorrhagic fever (DHF) and/or dengue shock syndrome (DSS)(2).Aedes mosquitoesare the principle vector in the broadcast ofdisease. This special mosquito is well adapted to humans and prefers to live in clean surroundings in closeproximity to clean human surroundings 8.Dengue virus serotypes were classified byAlbert Sabin in 1944.
(7) . Genetic diversityof dengue virus suggests its origin in Asia according to geographicdistribution .The first reported out-break of Dengue Hemorrhagic Fever (DHF)was from Philippine in 1953 7.Burden:Dengue virus infection isincreasingly recognized as one of the world’s emerging infectious diseases. Inannual report stated that about 50-100 million cases of dengue fever 500,000cases of Dengue Hemorrhagic Fever (DHFresulting in around 24,000 deaths20.After World war II insouth east Asia pandemic of dengue startand has spread around the globe .Dengue Hemorrhagic Fever (DHF) began a secondexpansion into Asia when Sri Lanka, India, and the Maldive Islands had their firstmajor DHF epidemics in 1980 20.
Local Occurrence: In Pakistan in 1994 first reported an epidemic of dengue fever.in othercountries like in Sri Lanka and Indiawere associated with multiple dengue virus serotypes, but DEN-3 was predominantand was genetically diverse from DEN-3 viruses previously isolated frominfected persons in those countries 20. In Asian countries last 15 years DengueHemorrhagic Fever is 20. In 2005, dengue is the most important mosquito-borneviral disease affecting humans 20.
Denguevirus is now widespread in Pakistan during in the post monsoon period. Recentflood in Pakistan made the situation inferior for Dengue according reportsof Surveillance Cell Sind20.Researchers have recognizedthat co-circulation of DEN-2 and DEN-3 was responsible for the 2006 out-breakin Karachi20. Introduction of a new serotype (DEN-3) serotype (DEN-2) are theprobable factors for the recent out-break of DHF in this region20.Life cycle of dengue:Blood cells and plasma are essential media for thefour serotypes of dengue virus (DENV1-4) spreading into an infected person.
Physiological changes often change the concentration of individual plasmacomponents, making plasma an important source of biomarkers for diseasediagnosis and prognosis. Aedes mosquitoes are the principle vector in the transmissionof disease. This special mosquito is well adapted to humans and prefers to livein clean surroundings in close proximity to clean human surroundings 8. Symptoms of dengue:Dengue patient have following signs:· severeabdominal pain, · persistent vomiting.· High temperature.· hemorrhagic signs.In Some patient of dengue go on to develop denguehemorrhagic fever (DHF).
dengue hemorrhagic fever is a severe and caused death7. Around thetime the fever begins to subside (usually 3–7 days after symptom onset), thepatient may develop warning signs of severe disease such as;· change in mental status (irritability,confusion, or obtundation)· restlessness,· cold clammy skin,· rapid weak pulse, · Narrowing of the pulse pressure.Transmission of dengue fever:The dengue virus is transmitted from oneperson to another person through the bite of an infected mosquito. Onlya few mosquito species are vectors for the dengue virus. A vector is a vehiclethat carries and transmits a disease to its host organism.
Vectors includeanimals and microorganisms that transmit different disease. Examples of vectorSuch as , ticks can transmit Lyme disease, and some mosquitoes can transmityellow fever, malaria, and dengue fever(www.nature.com/scitable/topicpage/dengue-) Mosquito AedesAegypti , which generally gets the virus while suckling on the blood of aninfected person and transfer the disease to another healthyperson20fig(1).
This mosquito rests in a cool and shaded places 20. Thefemale mosquito Aedes Aegypti lays her eggs in water containers inand around homes , schools and other areas in towns or villages. Approximately in10 days these eggs become adults. Dengue mosquitoes also breed in the water collectionsystems, barrels, drums, jars, pots, buckets, flower vases, plant saucers,tanks, waste bottles/tins, tires, or water coolers, and other places whererainwater collects or stored 20. Figure: Denguetransmission(https://www.nature.com/scitable/topicpage/dengue-transmission-22399758)The denguevirus is spread through a human-to-mosquito-to-human cycle of transmission(Figure 2). Typically, four days after being bit by an infected Aedesaegypti mosquito, a person will develop viremia, acondition in which there is a high level of the dengue virus in the blood.
Viremia lasts for approximately five days, but can last as long as twelve days.On the first day of viremia, the person generally shows no symptoms of dengue.Five days after being bit by the infected mosquito, the person developssymptoms of dengue fever, which can last for a week or longer.
Denguecan be transmitted during organ transplantations or blood transfusions frominfected donors. There is also evidence that an infected pregnant mother cantransmit the dengue virus to her fetus. Despite these rare events, the majorityof dengue infections are transmitted by mosquito (https://www.
nature.com/scitable/topicpage/dengue-transmission-22399758).Genomics and proteomics:DengueVirus Genome and Structure:The genome dengue virus is consist on a single strand of RNA . itcan be directly translated into proteins so referred to as positive-senseRNA.
The viral genome encodes ten genes (Figure 2). The genome istranslated as a single, long polypeptide and then cut into ten proteins. Figure2: Dengue virus genome(www.
nature.com/scitable/topicpage/dengue-) TheDENV genome is composed of a single positive-sense RNA that encodes a singleviral polyprotein that is further processed by viral and host proteases intothree structural proteins ( capsid, C; premembrane, prM envelope) andseven non-structural proteins (NS1,NS2A, NS2B, NS3, NS4A, NS4B, NS5).NS1 is the first non-structural protein whichis important for virus replication (www.
nature.com/scitable/topicpage/dengue). The nonstructural protein NS1 is an essential viral product implicated in DENVreplication and thepathogenesis of dengue hemorrhagic fever and dengue shock syndrome 3. DENV is anenveloped virus with an 11 kb single-stranded positive sense RNA 3.It is transferredto humans through the bite of mosquitoes of the Stegomyia genus, mostlyStegomyia (Aedes) aegypti, producing a wide spectrum of clinical manifestationsthat range from a mild self-limited febrile disease known as Dengue Fever (DF)to a hemorrhagic lifethreatening syndrome denominated Severe Dengue (SD)4.
InRNA replication Seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A,NS4B, NS5), 5′ and 3′ untranslated regions (UTR) are involved. The N-terminusof NS3 codes a serine protease essential virus replication 10. ImmunizationInlate 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) bySanofi Pasteur, was registered in several countries for use in individuals 9-45years of age living in endemic areas.WHOrecommends that countries should consider introduction of the dengue vaccineCYD-TDV only in geographic settings (national or subnational) whereepidemiological data indicate a high burden of disease. Dengue in pakinstan: Pakistan has experienced a number of dengue feveroutbreaks since 1992. In the 2005 Karachi outbreak 4,500 dengue cases were identified7.
Due to many congested cities, unsafe drinking water, poor sanitation,large number of refugees and low vaccination coverage Pakistan is at high riskof being hit by large epidemics. These conditions promote the spread ofinfectious diseases and consequently every year a large number of outbreaksoccur in different parts of the country, which result in increased disease and death19.Dengue virus is now common in Pakistan, circulating throughout the yearwith a peak incidence in the post monsoon period. Dengue in KPk: Protein–proteininteraction networks:Protein–proteininteraction networks are the networks of protein complexes formed by biologicalevents that performed a different biological .The protein interactome defines the full repertoire of a biologicalsystem’s protein–protein interactions (PPIs).
(https://www.nature.com/subjects/protein-protein-interaction-networks). Protein-protein interaction networks (PPIN) are mathematical representations of the physicalinteractions between proteins in the cell (https://www.ebi.
ac.uk/network-analysis-protein-interaction-data).Studying protein interaction networks of all proteins inan organism remains one of the major challenges in modern biomedicine. Suchinformation is essential to understanding cellular pathways and developingeffective therapies for the treatment of human diseases 11. A protein–proteininteraction (PPI) involves two or more proteins are fuse together, to performtheir biological function. A protein-protein interaction network (PPIN) is acollection of PPIs, that deposited in online databases (http://www.
bioforscher.de).Network science dealswith complexity by “simplifying” complex systems to nodes and (edges) betweenthem (Fig1.
). These simplifications help researchers make useful discoveries.Networks can be built purely based on gene expression information, includingtranscriptional regulatory networks and co-expression networks, or can also be constructedupon preceding knowledgeof protein–protein interactions.
The proteins in anetwork representation are metabolites or macromolecules such as proteins, RNAmolecules and gene sequences. The interactions are physical, biochemical orfunctional interactions 12. (fig1) Applicationsof PPI networks :Applications of PPI networksto disease datasets are focused on four major areas: (i) the identification ofgenes and proteins related with diseases, (ii) the study of network propertiesand their relation to disease states, (iii) the identification ofdisease-related subnetworks, and (iv) network-based disease classification.().
Protein networks areuseful resources to classify novel pathways to gain basic knowledge ofdiseases. Protein interaction sub networks are group of the proteins that areinteracting with each other’s in functional complexes and pathways. Now, newmethods are being developed to precisely extract interaction sub networks to producepathway hypotheses that can be used to understand different aspects of diseaseprogression .The Role of Networks inMedicine:Networks offer a systems-levelunderstandingof the mechanisms underlying diseases by serving as a model for dataintegration and analysis. They have been used to gain insight into disease mechanisms,study comorbidities , analyze therapeutic drugs and their targets, and discover new network-based biomarkers().