Introduction: in drug development, since drugs can affect

Introduction:

Background:

The title of this research is Protein-protein interaction networks (PPIN). Protein-protein interaction
networks (PPIN) is the mathematical representation of physical interaction
between proteins in the cell. These contacts are specific (www.ebi.ac.uk).It is
also essential in drug development, since drugs can affect PPIs.Dengue fever is
caused by Aedes aegypti mosquitoes which are the principle vector in the
transmission 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:

Dengue
creates a main public health problem in tropical and sub-tropical countries 1. Presently Dengue virus threatens half of the world’s
population and is a significant public health problem in many tropical regions
of the world 10. Genetic diversity of dengue virus suggests its origin in
Asia according to geographic distribution 7. Current  estimates show at least 390 million dengue
infections occurs annually, of which approximately
100 million are symptomatic 1. The infection is caused by dengue virus (DENV)
member of the Flaviviridae family that co-circulates in nature as four diverse
antigenic serotypes (DENV1 – 4) Dengue   
virus   (DEN-1, DEN-2, DEN-3, and DEN-4) caused dengue
infection in human body. These four viruses are different interaction with
antibody that’s why called   serotypes.
The four dengue viruses are 65% genomes are similar but there is slight genetic
variation in single serotype (/www.nature.com/scitable/topicpage/dengue-viruses) .Flaviviruses are
small, enveloped viruses with a single-stranded positive-sense RNA, which can
be translated into a single polyprotein by host cell proteins. The polyprotein
is then cleaved into distinct proteins by both viral and host proteases 4.
The dengue constitute three structural protein capsid, pre-membrane and
envelope (10).

DENV infection in humans is generally asymptomatic,
but symptomatic cases can diverge from a minor and self-limited fever to a
potentially fatal hemorrhagic syndrome 1. Dengue
virus (DENV) is the causative agent of dengue hemorrhagic fever and dengue shock
syndrome.  The human population globally
affecting potentially by these disease 1. Approximately 390 million people
acquire DENV infection through mosquito bites each year, and 96 million of them
present varying degrees of clinical manifestations 1. However, the underlying mechanisms of these severe dengue diseases remain unclear
and neither a dengue vaccine nor a specific antiviral drug is commercially
available 3.

Epidemiology:

In 1943 first time Ren
Kimura and Susumu Hotta isolated the dengue virus.These two scientist were
studying blood samples of patients taken during the epidemic in Nagasaki japan.
A year later, Albert B. Sabin and Walter Schlesinger independently isolated the
dengue virus(www.nature.com/scitable/).Infections caused by the
four serotypes of dengue  viruses borne
by the Aedes mosquito can result in dengue fever (DF), dengue
hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS)(2).Aedes mosquitoes
are the principle vector in the broadcast of
disease. This special mosquito is well adapted to humans and prefers to live in clean surroundings in close
proximity to clean human surroundings 8.
Dengue virus serotypes were classified by
Albert Sabin in 1944.(7) . Genetic diversity
of dengue virus suggests its origin in Asia according to geographic
distribution .The first reported out-break of Dengue Hemorrhagic Fever (DHF)
was from Philippine in 1953 7.

Burden:

Dengue virus infection is
increasingly recognized as one of the world’s emerging infectious diseases. In
annual report stated that about 50-100 million cases of dengue fever 500,000
cases of Dengue Hemorrhagic Fever (DHFresulting in around 24,000 deaths20.After World war II in
south east Asia  pandemic of dengue start
and has spread around the globe .Dengue Hemorrhagic Fever (DHF) began a second
expansion into Asia when Sri Lanka, India, and the Maldive Islands had their first
major DHF epidemics  in 1980 20.

Local Occurrence:

           In 
Pakistan in 1994 first reported an epidemic of dengue fever.in other
countries like  in Sri Lanka and India
were associated with multiple dengue virus serotypes, but DEN-3 was predominant
and was genetically diverse from DEN-3 viruses previously isolated from
infected persons in those countries 20. In Asian countries last 15 years Dengue
Hemorrhagic Fever is 20. In 2005, dengue is the most important mosquito-borne
viral disease affecting humans 20.Dengue
virus is now widespread in Pakistan during in the post monsoon period. Recent
flood in Pakistan made the situation inferior for Dengue according reports
of   Surveillance Cell Sind20.Researchers have recognized
that co-circulation of DEN-2 and DEN-3 was responsible for the 2006 out-break
in Karachi20. Introduction of a new serotype (DEN-3) serotype (DEN-2) are the
probable factors for the recent out-break of DHF in this region20.

Life cycle of dengue:

Blood cells and plasma are essential media for the
four serotypes of dengue virus (DENV1-4) spreading into an infected person.
Physiological changes often change the concentration of individual plasma
components, making plasma an important source of biomarkers for disease
diagnosis and prognosis. Aedes mosquitoes are the principle vector in the transmission
of disease. This special mosquito is well adapted to humans and prefers to live
in clean surroundings in close proximity to clean human surroundings 8.

Symptoms of dengue:

Dengue patient have following signs:

·       
 severe
abdominal pain,

·       
persistent vomiting.

·       
High temperature.

·       
hemorrhagic signs.

In Some patient of dengue go on to develop dengue
hemorrhagic fever (DHF).dengue hemorrhagic fever  is a severe and caused death7. Around the
time the fever begins to subside (usually 3–7 days after symptom onset), the
patient 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 one
person to another person   through the bite of an infected mosquito. Only
a few mosquito species are vectors for the dengue virus. A vector is a vehicle
that carries and transmits a disease to its host organism. Vectors include
animals and microorganisms that transmit different disease. Examples of vector
Such as , ticks can transmit Lyme disease, and some mosquitoes can transmit
yellow fever, malaria, and dengue fever(www.nature.com/scitable/topicpage/dengue-)

 Mosquito Aedes
Aegypti , which generally gets the virus while suckling on the blood of an
infected person and transfer the disease to another   healthy
person20fig(1). This mosquito rests in a cool and shaded places 20. The
female mosquito  Aedes  Aegypti lays her eggs in water containers in
and around homes , schools and other areas in towns or villages. Approximately in
10 days these eggs become adults. Dengue mosquitoes also breed in the water collection
systems, barrels, drums, jars, pots, buckets, flower vases, plant saucers,
tanks, waste bottles/tins, tires, or water coolers, and other places where
rainwater collects or stored 20.

 

Figure: Dengue
transmission(https://www.nature.com/scitable/topicpage/dengue-transmission-22399758)

The dengue
virus is spread through a human-to-mosquito-to-human cycle of transmission
(Figure 2). Typically, four days after being bit by an infected Aedes
aegypti mosquito, a person will develop viremia, a
condition 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 develops
symptoms of dengue fever, which can last for a week or longer.

 Dengue
can be transmitted during organ transplantations or blood transfusions from
infected donors. There is also evidence that an infected pregnant mother can
transmit the dengue virus to her fetus. Despite these rare events, the majority
of dengue infections are transmitted by mosquito (https://www.nature.com/scitable/topicpage/dengue-transmission-22399758).

Genomics and proteomics:

Dengue
Virus Genome and Structure:

The genome dengue virus is consist on a single strand of RNA . it
can be directly translated into proteins so referred to as positive-sense
RNA. The viral genome encodes ten genes (Figure 2). The genome is
translated as a single, long polypeptide and then cut into ten proteins.

Figure
2: Dengue virus genome(www.nature.com/scitable/topicpage/dengue-)

 

The
DENV genome is composed of a single positive-sense RNA that encodes a single
viral polyprotein that is further processed by viral and host proteases into
three structural proteins ( capsid, C; premembrane, prM envelope) and
seven  non-structural proteins (NS1,
NS2A, NS2B, NS3, NS4A, NS4B, NS5).NS1 is the first non-structural protein which
is important for virus replication (www.nature.com/scitable/topicpage/dengue). The nonstructural protein NS1 is an  essential viral product implicated in DENV
replication  and the
pathogenesis of dengue hemorrhagic fever and dengue shock syndrome 3. DENV is an
enveloped virus with an 11 kb single-stranded positive sense RNA 3.It is transferred
to humans through the bite of mosquitoes of the Stegomyia genus, mostly
Stegomyia (Aedes) aegypti, producing a wide spectrum of clinical manifestations
that range from a mild self-limited febrile disease known as Dengue Fever (DF)
to a hemorrhagic lifethreatening syndrome denominated Severe Dengue (SD)4. In
RNA replication Seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A,
NS4B, NS5), 5′ and 3′ untranslated regions (UTR) are involved. The N-terminus
of NS3 codes a serine protease essential virus replication 10.

 

 

Immunization

In
late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by
Sanofi Pasteur, was registered in several countries for use in individuals 9-45
years of age living in endemic areas.

WHO
recommends that countries should consider introduction of the dengue vaccine
CYD-TDV only in geographic settings (national or subnational) where
epidemiological data indicate a high burden of disease.

 

Dengue in pakinstan:

Pakistan has experienced a number of dengue fever
outbreaks since 1992. In the 2005 Karachi outbreak 4,500 dengue cases were identified
7. Due to many congested cities, unsafe drinking water, poor sanitation,
large number of refugees and low vaccination coverage Pakistan is at high risk
of being hit by large epidemics. These conditions promote the spread of
infectious diseases and consequently every year a large number of outbreaks
occur in different parts of the country, which result in increased disease and death
19.Dengue virus is now common in Pakistan, circulating throughout the year
with a peak incidence in the post monsoon period.

Dengue in KPk:

 Protein–protein
interaction networks:

Protein–protein
interaction networks are the networks of protein complexes formed by biological
events that performed a different biological .The protein interactome  defines the full repertoire of a biological
system’s protein–protein interactions (PPIs).(https://www.nature.com/subjects/protein-protein-interaction-networks). Protein-protein interaction networks (PPIN) are mathematical representations of the physical
interactions between proteins in the cell (https://www.ebi.ac.uk/network-analysis-protein-interaction-data).

Studying protein interaction networks of all proteins in
an organism remains one of the major challenges in modern biomedicine. Such
information is essential to understanding cellular pathways and developing
effective therapies for the treatment of human diseases 11. A protein–protein
interaction (PPI) involves two or more proteins are fuse together, to perform
their biological function. A protein-protein interaction network (PPIN) is a
collection of PPIs, that deposited in online databases (http://www.bioforscher.de).

Network science deals
with complexity by “simplifying” complex systems to nodes and (edges) between
them (Fig1.). These simplifications help researchers make useful discoveries.
Networks can be built purely based on gene expression information, including
transcriptional regulatory networks and co-expression networks, or can also be constructed
upon preceding knowledgeof protein–protein interactions. The proteins in a
network representation are metabolites or macromolecules such as proteins, RNA
molecules and gene sequences. The interactions are physical, biochemical or
functional interactions 12.

(fig
1)

 

 

Applications
of PPI networks :

Applications of PPI networks
to disease datasets are focused on four major areas: (i) the identification of
genes and proteins related with diseases, (ii) the study of network properties
and their relation to disease states, (iii) the identification of
disease-related subnetworks, and (iv) network-based disease classification.().

Protein networks are
useful resources to classify novel pathways to gain basic knowledge of
diseases. Protein interaction sub networks are group of the proteins that are
interacting with each other’s in functional complexes and pathways. Now, new
methods are being developed to precisely extract interaction sub networks to produce
pathway hypotheses that can be used to understand different aspects of disease
progression .

The Role of Networks in
Medicine:

Networks offer a systems-level
understandingof the mechanisms underlying diseases by serving as a model for data
integration 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().