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Dengue was foremost reported in 1779 with the visual aspect of a dengue-like disease ; nevertheless research workers suggest that it has been about longer than that ( Gupta, 2006 ) . Harmonizing to CDC, over 100 million people world-wide get infected with the Dengue virus ( CDC 2010 ) . Dengue is caused by the Dengue virus and is one of the most lifelessly infective disease in India. It has been known to do an epidemic at that place. In topographic points like India and other developing states in South Asia, Dengue febrility spreads due to the overpowering mosquito populations in dead H2O found on the waysides and rubbish disposal countries ( Gupta et al, 2006 ) . Mosquitoes breed in this dead H2O and when these mosquitoes bite people, the person that was bit gets Dengue Fever which can so take to a more serious manifestation if non resolved by the person ‘s immune system, viz. : Dengue Hemorrhagic Fever and subsequently Dengue Shock Syndrome ( Gupta et al, 2006 ) . Dengue virus infection does non distribute from individual to individual ( Gupta et al, 2006 ) . Nevertheless, due to hapless hygiene patterns ensuing in over genteelness of Dengue virus transporting mosquito vectors, Dengue infection is a menace in India and its surrounding states ( Gupta et al, 2006 ) .

This paper will present the Dengue virus and its belongingss, its generative rhythm in the host, its virulency and the mechanism by which Dengue Fever can attest onto Dengue Hemorrhagic Fever and Dengue Shock Syndrome. Hosts protection schemes against this virus every bit good as host mediated sweetening of virulency will besides be discussed.

Dengue viruses are individual isolated plus sense RNA viruses belonging to the flaviviridae household ( Lindabach et al, 2003 ) . Morphologically, they are little, enveloped and icosahedral. They belong to group IV under the Baltimore Classification system ( Lindabach et al, 2003 ) . The genome is about 10700 bases in length surrounded by a nucleocapsid and covered by a lipid envelope incorporating the envelope and the membrane proteins ( Clyde et al, 2006 ) . The genome has a individual unfastened reading frame which encodes a precursor polyprotein and is flanked by two non-translated parts ( Clyde et al, 2006 ) . This cistron so undergoes translational and post-translational proteolytic cleavage of the precursor. Cleavage gives rise to the three structural proteins: mirid bug ( C ) , membrane ( M ) and envelope ( E ) and seven non-structural proteins: NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5 ( Zybert et Al, 2010 ) . From these proteins, the 1s that are of import for virulency are E, prM, NS1 and NS3 cistrons. These proteins are used to originate and keep infection in hosts ( Zybert et Al, 2010 ) .

Most of the Dengue virus infection is reported in Tropical countries- Caribbean part, South America, Africa and South Asia ( CDC 2009 ) . This is because the virus vector which is a mosquito requires a warm clime ( CDC 2009 ) . Dengue virus is transmitted to people through the bites of mosquitoes: Aedes aegypti and Aedes albopictes ( CDC 2009 ) . The virus is transmitted when a mosquito of the Aedes genus bites a individual infected with dandy fever virus ( CDC 2009 ) . Basically, the virus in the blood of the septic single infects the mosquito and travels from the mosquito ‘s intestine to its salivary secretory organs where the virus multiplies. So, the following clip when this mosquito bites another individual, the virus is injected into the individual ( CDC 2009 ) . Mosquito transmits the disease by forestalling blood coagulating when feeding on the individual ; so the individual gets the dandy fever virus. Equally long as the mosquito is alive, it retains the virus and is able to infect another individual with the Dengue virus ( CDC 2009 ) .

In recent old ages, Dengue virus has been a immense concern in developed states in North America and Europe because scientists fear that the mosquitoes will be able to defy ice chest climes and be able to infect people in temperate climes as good ( Zybert et Al, 2010 ) . Dengue virus is now believed to be the most common arthropod-borne viral infection in the universe ( CDC 2010 ) . This virus infects a broad scope of hosts ; from mosquitoes to worlds, hamsters and gnawers. This implies they do non truly hold a penchant ; they will be deadly and transmitted through the mosquito vector whenever the mosquito bites its prey- homo or animate being ( CDC 2010 ) .

Dengue virus has 4 antigenic serotypes. These 4 serotypes are different strains of Dengue virus but they have about 60-80 % homology between each other ( Clyde et al, 2006 ) . All four Dengue virus serotypes are prevailing in the sub-tropical parts of the universe ( CDC 2010 ) . The bulk of the Dengue virus infection returns without symptoms or consequence in self-limited dandy fever febrility ( Clyde et al, 2006 ) . This is because the septic person ‘s immune system successfully resolves the infection. But the job arises when patients show a more serious manifestation of this virus that causes Dengue Hemorrhagic Fever ( DHF ) and the Dengue Shock Syndrome ( DSS ) ( Clyde et al, 2006 ) . Majority of decease that consequences from dengue infection is hence non due to the more common Dengue febrility ( DF ) but due to DHF ; there is a 5 % opportunity of human death with DHF but if the patient goes onto develop DSS, so the human death reaches every bit high as 40 % ( CDC 2010 ) .

After the individual gets infected, the incubation period of the Dengue Virus is about 4 yearss ( Zybert et Al, 2010 ) . The individual will come down with febrility and mild flu-like symptoms every bit good as nowadays a macular or maculopapular roseola. During this clip, it is hard to separate dandy fever febrility from other viral diseases and the individual normally recovers in 5 yearss ( Zybert et Al, 2010 ) . In a more terrible instance, febrility and roseola are accompanied by concern, myodynia, backache, sore pharynx and abdominal hurting. The patients besides become unenrgetic and experience anorexia and sickness. DHF has a similar incubation period as dandy fever febrility and many of the same symptoms. However, the febrility is more terrible and the other mentioned symptoms are more utmost ( Zybert et Al, 2010 ) . The patient undergoes increased vascular permeableness: plasma escape, loss of endothelial unity and unnatural homeostasis. This causes the patient to lose more blood, experience high blood pressure, travel into Dengue Shock Syndrome and dice ( CDC 2009 ) . This means DF when unresolved by the hosts ‘ immune system leads to DHF and when the loss of blood during DHF is utmost ; the patient undergoes DSS and dies if immediate medical attending is non given ( CDC 2009 ) . Therefore, Dengue virus infections can be subclinical or cause unwellnesss runing from mild, flu-like symptoms with roseola ( DF ) to a terrible and sometimes fatal disease characterized by capillary escape and systemic daze ( CDC 2009 ) .

Besides, it is of import to observe here that infection with one dandy fever virus serotype does non confabulate protective or long-run unsusceptibility against other serotypes ( Clyde et al, 2006 ) . Besides, unlike the immune system ‘s interaction with other disease doing pathogens, where secondary infection with the same pathogen is less terrible and rapidly resolved, in the instance of Dengue virus ; secondary infection is much worse ( Clyde et al, 2006 ) . The mechanism through which this happens is termed Antibody-Dependent Enhancement or ADE. ADE is mediated by host ‘s ain immune system which increases the activity of immune cell proteins like interferons, cytokines, compliment which so increase the loss of endothelial unity and capillary permeableness of the plasma membrane escape is a trademark of DHF ( Clyde et al, 2006 ) .

Naturally, immune system cells like macrophage, monocytes and dendritic cells are the marks for Dengue infection ( Lindabach et al, 2003 ) . Dengue virus reproduction involves the same general stairss used by other RNA viruses: Dengue virus attaches to the host cell surface, enters the cytol, translates its viral proteins, replicates its RNA viral genome, signifiers virions with mirid bugs and so eventually exits from the cell ( Lindabach et al, 2003 ) . Specifically, Dengue virus binds to the cell by utilizing its major viral envelope ( E ) glycoprotein. This protein is perfectly indispensable for infectivity ( Zybert et Al, 2010 ) . The E binds to the viral receptors on the cell surface which is normally a heparin sulphate or the high-affinity laminin receptor ( Zybert et Al, 2010 ) . Like other Flaviviruss, Dengue virus besides uses clathrin-mediated endocytosis for cell entry ( Lindabach et al, 2003 ) . The merger of viral and cellular membranes is mediated by the low pH/acidified cysts of the endosome. After the merger, the viral RNA enters the cytol of the host cell ( Lindabach et al, 2003 ) . Then it uncoats its nucleocapsid ; after uncoating, the RNA molecule is translated as a individual polyprotein ( Lindabach et al, 2003 ) . The polyprotein so gets processed into 3 structural and 7 non-structural proteins mentioned above. The cleavage of several of the viral proteins requires a functional viral peptidase that is encoded in the nonstructural protein NS3 ( Zybert et Al, 2010 ) . The non-structural protein NS5 is the RNA-dependent RNA polymerase which assembles with several other viral proteins and host proteins to organize the reproduction composite ( Zybert et Al, 2010 ) . This composite is the 1 responsible for transcribing the viral RNA to bring forth negative-strand viral RNA which so serves as a templet for the production of the viral genome ( Zybert et Al, 2010 ) .

The first line of defence against Dengue viral infection is the production of interferons by the hosts ‘ immune system ( Clyde et al, 2006 ) . Interferon mediated immune responses create an anti-viral province and originate a assortment of procedures including metabolic control to restrict virus infection. Besides, these responses trigger the adaptative immune response ( B cells and T cells ) to step in and take action. Humoral unsusceptibility which is another term for B cell response or antibody response takes topographic point six yearss post bite from the infected mosquito ( Clyde et al, 2006 ) . The antibody response is chiefly directed against the E and the prM glycoproteins present on the surface of the virus. In making so, antibodies suppress the virulency of the virus by neutralizing the viral antigens ( Clyde et al, 2006 ) . Hence, merely a mild Dengue febrility or symptomless Dengue infection is the consequence. Neutralizing antibodies fundamentally block the fond regard of the virus to its natural receptor on the cell surface or suppress subsequent stairss in the entry procedure of the virus ( Clyde et al, 2006 ) . However, in the worst instance scenario, the same protective antibodies can heighten virus infectivity and cause DHF or even worse, DSS ( Clyde et al, 2006 ) .

Surveies have shown that secondary infection with a different Dengue virus serotype or first clip infection of babies born to dengue immune female parents extremely increases the hazard to develop terrible disease ( Zybert et Al, 2010 ) . These observations have led to the Antibody-Dependent Enhancement hypothesis of Dengue virus infection ( Zybert et Al, 2010 ) . Studies with E-specific antibodies have shown that when the virus antigen neutralisation by the B cell antibody occurs at a threshold lower than the 1 required for virus neutralisation ; these antibodies particularly direct the virus particles to cells with FcR receptors ; these FcR receptors are normally the natural marks of the virus, so directing the virus towards them is a bad move ( Zybert et Al, 2010 ) . Macrophages, monocytes and dendritic cells all have FcR. Binding of the virus antigen to the FcR on these phagocytic cells facilitates the entry of virions via FcR mediated endocytosis ( Clyde et al, 2006 ) . To this day of the month, the molecular mechanisms underlying antibody-dependent sweetening has non been uncovered ( Zybert et Al, 2010 ) . .

Consumption of the Dengue virus-immune composites via FcR mediated entry non merely leads to a higher figure of septic cells but it can besides increase the figure of virus atoms produced per infected cell ( Zybert et Al, 2010 ) . So far, most of the research has focused on innate and humoral unsusceptibility against Dengue Virus ( Zybert et Al, 2010 ) . However, a recent survey on T cell response has shown that CD8 ( cytotoxic ) cells particularly known for their violent death of virally septic cells fight against Dengue infection and in making so bring on a cytokine storm – monolithic release of inflammatory cytokines into the hosts ‘ organic structure ( Zybert et Al, 2010 ) . However, this does more injury to the host than good. The trademark of DHF/DSS is the loss of endothelial unity which is due to the unnatural immune response to the virus ( Zybert et Al, 2010 ) . Clinical surveies have shown that patients enduring from DHF/DSS show a enormous addition in all major cytokines, i.e. TNF-a, IL-1b, IL-4, IL-6 etc ( Zybert et Al, 2010 ) . Both the ADE and cytokine storm theories suggest that the aggravation of Dengue infection is non because of the virus itself but more due to the immune system ‘s response to the infection.

Apart from the immune system, there are other factors besides involved in commanding Dengue virus infection. Each Dengue virus serotype ( there are a sum of 4 ) have multiple genotypes ( CDC 2010 ) . Research has shown that some genotypes are more associated with DHF than others ( Zybert et Al, 2010 ) . These genotypes are: DENV-2 and DENV-3. The first eruption of DHF in the Americas happened at the same clip as the debut of the DENV-2 Southeast Asia genotype did ( Zybert et Al, 2010 ) . In America, this DENV-2 genotype about entirely caused Dengue febrility and non Dengue hemorrhagic febrility ( Zybert et Al, 2010 ) . But in Southeast Asia, the same genotype caused DHF ( Zybert et Al, 2010 ) . This showed that the Southeast Asiatic DENV-2 genotype is more unsafe than the DENV-2 genotype in the Americas ( Zybert et Al, 2010 ) . This suggests that the same Dengue virus genotype can ensue in different pathological conditions depending on the geographical locations ( Zybert et Al, 2010 ) . When elaborate genomic analysis was done on the Asian and the American genotype of the DENV-2, nucleotide differences were seen in the cistrons of the of import viral proteins ( Zybert et Al, 2010 ) . It was besides shown that the Southeast Asiatic DENV-2 genotype had a higher reproduction rate in human macrophages and dendritic cells compated to the American DENV-2 genotype ( Zybert et Al, 2010 ) . .

Second, virulency is besides enhanced due to glycosylation of the E and NS1 proteins ( Zybert et Al, 2010 ) . Glycosylation refers to add-on of saccharides. Glycosylation consequences in a stable adhering interaction between the virus E protein and the DC-SIGN of the dendritic cells in host doing the receptor mediated endocytic merger much easier ( Zybert et Al, 2010 ) .

Finally, non all persons respond to the Dengue virus infection in the same manner. Differences in disease symptoms are besides seen within certain human populations ( Zybert et Al, 2010 ) . No Dengue hemorrhagic febrility or Dengue daze syndrome was seen in Haitian population despite infection by several Dengue serotypes ( Zybert et Al, 2010 ) . Besides, it was shown that Black people developed terrible dandy fever less often than White people ( Zybert et Al, 2010 ) . This caused the scientists to speculate that fluctuation in cistrons and cistron mutants contribute to the variable susceptibleness to Dengue virus in worlds ( Zybert et Al, 2010 ) .

Some cistrons have in fact been implicated in confabulating protection against terrible Dengue infection every bit good as doing persons susceptible to severe Dengue infection ( Zybert et Al, 2010 ) . The cistrons that do this are both from the Human Leukocyte Antigen ( HLA ) household of immune system cistrons. It was found that people with HLA category I allelomorphs: A*01, A*0207, A*24, B*07, B*46, B*51 and HLA category II alleles like DQ*1, DR*1 and DR*4 were associated with terrible Dengue virus infection. On the contrary, persons showing HLA-B*13, HLA-B*14 and HLA-B*29 were found to be protected against terrible Dengue virus infection ( Zybert et Al, 2010 ) .

There are besides other host factors that confer different degree of unsusceptibility or susceptibleness to Dengue infection. Peoples with glucose 6-phosphate dehydrogenase lack have a higher hazard of developing DHF upon Dengue virus infection ( Zybert et Al, 2010 ) . This was known because the monocytes taken from these persons supported a higher than normal reproduction rate for the Dengue virus ( Zybert et Al, 2010 ) . Besides, immunocompromised persons like the 1s enduring from diabetes mellitus are more susceptible to develop terrible Dengue ( Zybert et Al, 2010 ) . An account for this phenomenon was that there is an addition in the production of cytokines in diabetes mellitus patients and this makes them more prone to vascular escape. This escape as mentioned already is an of import feature of DHF ( Zybert et Al, 2010 ) .

Despite the find of many familial and environmental factors every bit good as many host and viral proteins being uncovered ; it is really hard to nail at the exact interaction between the Dengue virus and the immune system cells in natural hosts. A deficiency of a better carnal theoretical account exacerbates the state of affairs. Hence, it is hard to explicate molecularly why ADE is initiated and how ADE leads to Dengue hemorrhagic febrility and Dengue daze syndrome ( Zybert et Al, 2010 ) .

To repeat, after a individual is infected with dandy fever virus, they develop an immune response to that peculiar dandy fever serotype. The immune response produces specific antibodies to that serotype ‘s surface proteins that prevent the virus from adhering to the macrophage cells of the host and gaining entry. Therefore in mild instances of Dengue virus infection, the host ‘s immune system resolves the infection on its ain with merely the Dengue Fever as an result. However, if another serotype of Dengue virus infects the same individual, the virus will trip the immune system to assail it as if it were the first serotype. The immune system becomes confused because the four serotypes have really similar surface proteins/antigens. The antibodies bind to the surface antigens but do non demobilize the virus. Alternatively, ADE follows and FcR on phagocytic cells are turned on. This makes the viral infection much more terrible. The organic structure so releases cytokines that cause the endothelial tissue to go permeable which consequences in haemorrhagic febrility and unstable loss from the blood vass.

Due to the presence of the four similar but antigenically distinguishable Dengue virus serotypes, Vaccine development has been really hard ( Clyde et al, 2006 ) . As mentioned earlier, if a individual develops unsusceptibility to one serotype and so attempts to establish an immune response to another serotype, so the individual will acquire Dengue hemorrhagic Fever every bit good as might acquire Dengue Shock Syndrome subsequently ( Clyde et al, 2006 ) . As of now, research workers are working on doing a tetravalent vaccinum that works against all four serotypes ( CDC 2010 ) . So far, the lone manner to protect oneself from dandy fever virus infection is mosquito control which has been proven to be rather hard in states like India due to hapless sanitation patterns every bit good as the costs of mosquito repellant being high ( Gupta et al, 2006 ) .

As of now, there are non many intervention options available ( CDC 2006, 2010 ) . After infection with Dengue virus and enduring from Dengue hemorrhagic febrility, the chief precedence is to stabilise the plama membrane ‘s permeableness in order to avoid plasma escape and later forestalling the patient from traveling to DSS ( CDC 2010 ) . For this ground, patients enduring from Dengue Hemorrhagic Fever are given drugs like corticoids or carbazochrome Na sulfonate ( CDC 2010 ) . However, in poorer parts of India and its adjacent states, health care and drugs are unaccessible due to miss of conveyance every bit good as money ; therefore there is a high human death rate if the patient goes into DHF ( Gupta et al, 2006 ) .

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