Abstract:. Dengue is a vector-borne-disease. It is tran

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Abstract:Dengue is a vector-borne-disease. It is transmitted to human by mosquito bite.Dengue is one of the most important tropicaland sub-tropical diseases but is now spreading globally as a result of climate change, urbanization and international travel.Hence, there is a pressing need to control the spread of Dengue virus and to treat Dengue diseases. To be able to infect thehost Dengue virus must recognize host cell surface receptor(s) using virus-encoded envelope protein. Therefore,identification of virus receptor is very important in understanding the infection process and the development of anti-viralsand vaccine. However, not too much is known about Dengue receptors in the insect and human hosts. All putative Denguereceptors to date are poorly characterized. The aim of project is to identify and characterize bona fide Dengue receptor usinga range of stringent molecular and cellular techniques. Using a state-of-the art CRISPR genome editing tool we havesuccessfully knockout a putative Dengue receptor from a mosquito cell line. CRISPR is a recent, very powerful and yet simpleand versatile genome editing tool to silence specific genes in the genome. The CRISPR/Cas9 system was discovered inbacteria/Archaea as a defence mechanism against phage (virus) infections. It has now been repurposed as a gene editing toolin various organisms throughout the tree of lifeDengue Fever:Dengue virus is a single-stranded RNA virus of the Flavivirus genus and the Flaviviridae family. Dengue is a mosquito-borneviral disease that has rapidly spread in all regions of WHO in recent years. Dengue virus is transmitted by female mosquitoesmainly of the species Aedes aegypti and, to a lesser extent, Ae. albopictus. This mosquito also transmits chikungunya, yellowfever and Zika infection. Dengue is widespread throughout the tropics, with local variations in risk influenced by rainfall,temperature and unplanned rapid urbanization.Severe dengue (also known as Dengue Haemorrhagic Fever) was first recognized in the 1950s during dengue epidemics inthe Philippines and Thailand. Today, severe dengue affects most Asian and Latin American countries and has become aleading cause of hospitalization and death among children and adults in these regions.There are four distinct, but closely related, serotypes of the virus that cause dengue (DEN-1, DEN-2, DEN-3 and DEN-4).Recovery from infection by one provides lifelong immunity against that particular serotype. However, cross-immunity to theother serotypes after recovery is only partial and temporary. Subsequent infections by other serotypes increase the risk ofdeveloping severe dengue.Lifecycle:Dengue virus is maintained in the urban lifecycle as it is transmitted from mosquito to human to mosquito. The primarymosquito vector of dengue virus is Aedes aegypti .However, Aedes albopictus also transmits the virus (Brooks, Carroll, Butel,Morse, & Mietzner, 2010). Dengue virus is transmitted from human to mosquito when a female mosquito feeds on a viremichuman. The incubation period within the mosquito lasts 8-12 days and consists of the virus spreading systemically from themid-gut. After this period of time, the virus can be transmitted to another human during any point in the remainder of themosquito’s life (WHO,TDR, 2009).Global burden of dengue:The incidence of dengue has grown dramatically around the world in recent decades. The actual numbers of dengue casesare underreported and many cases are misclassified. One recent estimate indicates 390 million dengue infections per year(95% credible interval 284–528 million), of which 96 million (67–136 million) manifest clinically (with any severity ofdisease).1 Another study, of the prevalence of dengue, estimates that 3.9 billion people, in 128 countries, are at risk ofinfection with dengue viruses.2
Member States in 3 WHO regions regularly report the annual number of cases.. The number of cases reported increasedfrom 2.2 million in 2010 to 3.2 million in 2015. Although the full global burden of the disease is uncertain, the initiation ofactivities to record all dengue cases partly explains the sharp increase in the number of cases reported in recent years.Other features of the disease include its epidemiological patterns, including hyper-endemicity of multiple dengue virusserotypes in many countries and the alarming impact on both human health and the global and national economies.Before 1970, only 9 countries had experienced severe dengue epidemics. The disease is now endemic in more than 100countries in the WHO regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific.The America, South-East Asia and Western Pacific regions are the most seriously affected.Cases across the Americas, South-East Asia and Western Pacific exceeded 1.2 million in 2008 and over 3.2 million in 2015(based on official data submitted by Member States). Recently the number of reported cases has continued to increase. In2015, 2.35 million cases of dengue were reported in the Americas alone, of which 10 200 cases were diagnosed as severedengue causing 1181 deaths.Not only is the number of cases increasing as the disease spreads to new areas, but explosive outbreaks are occurring. Thethreat of a possible outbreak of dengue fever now exists in Europe as local transmission was reported for the first time inFrance and Croatia in 2010 and imported cases were detected in 3 other European countries. In 2012, an outbreak of dengueon the Madeira islands of Portugal resulted in over 2 000 cases and imported cases were detected in mainland Portugal and10 other countries in Europe. Among travellers returning from low- and middle-income countries, dengue is the second mostdiagnosed cause of fever after malaria.In 2013, cases have occurred in Florida (United States of America) and Yunnan province of China. Dengue also continues toaffect several South American countries, notably Costa Rica, Honduras and Mexico. In Asia, Singapore has reported anincrease in cases after a lapse of several years and outbreaks have also been reported in Laos. In 2014, trends indicateincreases in the number of cases in the People's Republic of China, the Cook Islands, Fiji, Malaysia and Vanuatu, with DengueType 3 (DEN 3) affecting the Pacific Island countries after a lapse of over 10 years. Dengue was also reported in Japan after alapse of over 70 years.In 2015, Delhi, India, recorded its worst outbreak since 2006 with over 15 000 cases. The Island of Hawaii, United States ofAmerica, was affected by an outbreak with 181 cases reported in 2015 and ongoing transmission in 2016. The Pacific islandcountries of Fiji, Tonga and French Polynesia have continued to record cases. The year 2016 was characterized by largedengue outbreaks worldwide. The Region of the Americas region reported more than 2.38 million cases in 2016, where Brazilalone contributed slightly less than 1.5 million cases, approximately 3 times higher than in 2014. 1032 dengue deaths werealso reported in the region. The Western Pacific Region reported more than 375 000 suspected cases of dengue in 2016, ofwhich the Philippines reported 176 411 and Malaysia 100 028 cases, representing a similar burden to the previous year forboth countries. The Solomon Islands declared an outbreak with more than 7000 suspected. In the African Region, BurkinaFaso reported a localized outbreak of dengue with 1061 probable cases.In 2017 (as of Epidemiological Week 11), the Region of Americas have reported 50 172 cases of dengue fever, a reduction ascompared with corresponding periods in previous years. The Western Pacific Region has reported dengue outbreaks inseveral Member States in the Pacific, as well as the circulation of DENV-1 and DENV-2 serotypes.Transmission:The Aedes aegypti mosquito is the primary vector of dengue. The virus is transmitted to humans through the bites ofinfected female mosquitoes. After virus incubation for 4–10 days, an infected mosquito is capable of transmitting the virusfor the rest of its life. Infected symptomatic or asymptomatic humans are the main carriers and multipliers of the virus,serving as a source of the virus for uninfected mosquitoes. Patients who are already infected with the dengue virus can
transmit the infection (for 4–5 days; maximum 12) via Aedes mosquitoes after their first symptoms appear. The Aedesaegypti mosquito lives in urban habitats and breeds mostly in man-made containers. Unlike other mosquitoes Ae. aegypti is aday-time feeder; its peak biting periods are early in the morning and in the evening before dusk. Female Ae. aegypti bitesmultiple people during each feeding period. Aedes albopictus, a secondary dengue vector in Asia, has spread to NorthAmerica and more than 25 countries in the European Region, largely due to the international trade in used tyres (a breedinghabitat) and other goods (e.g. lucky bamboo). Ae. albopictus is highly adaptive and, therefore, can survive in coolertemperate regions of Europe. Its spread is due to its tolerance to temperatures below freezing, hibernation, and ability toshelter in microhabitats.Manifestations:Dengue virus infections can manifest in different ways. Those infected may be asymptomatic, or have manifestationsconsistent with classic dengue fever, or dengue hemorrhagic fever with or without dengue shock syndrome (Table 1). TheWHO divides the course of dengue illness into 3 phases: febrile, critical, and recovery. After an incubation period of 4-10days, the febrile phase of dengue fever begins. There is a sudden onset of high-grade fever, and patients often experienceheadache, retro-orbital pain, myalgias, arthralgias, and facial flushing. Many complain of nausea, vomiting, and loss ofappetite. Less commonly, sore throat,injected pharynx, and conjunctivitis are noted. There may be mild hemorrhagicmanifestations such as petechiae, epistaxis and gingival bleeding and rarely gastrointestinal and vaginal bleeding. Also duringthis time, there may be hepatomegaly and a steady decrease in the white blood cell count. The febrile phase lasts 2-7 days.At this point, it cannot be determined which cases will become severe dengue fever (WHO, 1997; WHO, TDR, 2009).The critical phase begins around days 3-7 when the temperature decreases to and remains at 37.5-38C or less. During thistime, there may be an increase in capillary permeability leading to an increase in hematocrit (WHO, TDR, 2009). An increasein capillary permeability and plasma leakage is considered dengue hemorrhagic fever (WHO, 1997). One point to note is thatbefore plasma leakage occurs, there is a steady drop in total WBC count and a rapid drop in platelet count. If there is noincrease in capillary permeability, the patient improves and is considered to have had non-severe dengue infection. Severedengue occurs with the manifestation of at least one of the following: plasma leakage with or without shock, severebleeding, or severe organ impairment (WHO, TDR, 2009). A chest X-ray or an abdominal ultrasound may be useful inidentifying cases of severe dengue, as those with an increase in capillary permeability may develop pleural effusion andascites (WHO, TDr, 2009). In addition to labs showing leucopenia and thrombocytopenia, there will be hemoconcentration asdemonstrated by an elevation in hematocrit (WHO, 1997).Dengue shock syndrome occurs when excessive amounts of plasma are leaked into the extravascular space. This may occuraround day 4-5 or when the fever drops (WHO, TDR, 2009). Patients will exhibit signs of circulatory failure including cool,blotchy, and edematous skin, circumoral cyanosis, tachycardia, weak pulse, and a narrowing pulse pressure (WHO,1997). It isimportant to note that the diastolic blood pressure rises as the systolic blood pressureremains the same. This can be easilyoverlooked if the systolic blood pressure is within the normal range. However, the narrowing of the pulse pressure is awarning sign of shock and the patient needs prompt and adequate care. Shock is defined by a pulse pressure of less than orequal to 20mm Hg (WHO, TDR, 2009). If shock is treated, recovery can take place over 2-3 days (WHO, 1997). Multiple organfailure, metabolic acidosis, and disseminated intravascular coagulation can occur if shock is not recognized and treatedaggressively. Lastly, severe hemorrhages and death may occur (WHO, TDR, 2009).With proper monitoring and management, the recovery phase will commence consisting of resorption of the extravascularfluid within 48-72 hours. Symptoms improve and the patient returns to hemodynamic stability. The hematocrit, WBC count,and platelet count reach normal levels (WHO, TDR, 2009).The prognosis of dengue fever is good. There is the potential for the sequelae of prolonged fatigue and depression in somecases. In DHF, the case fatality rate is less than 1% (WHO, 1997). Rare but severe complications of dengue fever that canoccur even without plasma leakage and shock are hepatitis, encephalitis, myocarditis (WHO, TDR, 2009). CNS manifestations
of convulsions, spasticity, altered consciousness, and transient paralysis have been seen in some cases. Acute renal failureand hemolytic uremic syndrome are other rare findings (WHO, 1997).Treatment:The clinical course of dengue virus infection varies, and therefore, treatment is determined individually depending on apatient’s status. The most important aspects of treating a patient with DF are to recognize early signs of plasma leakage andto begin fluid therapy. A healthcare provider (HCP) must also recognize dengue shock syndrome and aggressively address theissues of shock, bleeding, and organ impairment (WHO, TDR, 2009).The decision to send a patient with DF home can be made if the patient is able to maintain adequate levels of fluid intakeand output. The patient must also have stable hematocrit levels and show no warning signs of severe dengue. A treatmentplan consists of fever controland drinking plenty of fluids containing electrolytes and sugar. NSAIDs are contraindicated dueto the potential for hemorrhagic manifestations. Patients must meet with their HCP on a daily basis to be assessed for signsof illness progression. It is essential for HCPs to educate their patients on warning signs that necessitate prompt medicalattention. These warning signs include shortness of breath, a fast pulse, severe abdominal pain, persistent vomiting,jaundice, cool and clammy extremities, lethargy, irritability, convulsions, significant bleeding (i.e. coffee-ground emesis orblack stools), and no urine output for 4-6 hours (WHO, TDR, 2009).Patients may be admitted if warning signs are present, if there are co-existing conditions, or if they do not have a caregiverat home or means of transportation to a hospital should they experience warning signs. Pregnant women as well as infantswith dengue virus infection should also be admitted. For a patient with warning signs, first the hematocrit must be measuredand then IV fluids should be aggressively administered. The patient’s status and hematocrit levels must be reevaluated andIV infusion rates may be adjusted accordingly. Vital signs and peripheral perfusion should be monitored until the patient hasadvanced to the recovery phase. Urine output, blood glucose, and organ function should also be monitored. In a patient whois admitted without warnings signs of severe dengue, IV fluid therapy should only be started if the patient cannot tolerateoral fluids. HCPs should watch for warning signs of severe dengue and measure the patient’s temperature, fluid intake andurine output, hematocrit and WBC and platelet counts (WHO, TDR, 2009).The last category of treatment is for those in the critical phase of dengue fever. Patients in the critical phase needemergency hospitalization. Those in this category have one or more of the following manifestations: dengue shock and/orfluid accumulation leading to respiratory distress, severe hemorrhage, and severe organ impairment. IV fluid resuscitation isessential and usually is the only intervention necessary for treatment of this phase. The goals of fluid resuscitation are toimprove central and peripheral circulation and organ perfusion. If a patient is in shock, IV fluid resuscitation should bestarted and the patient must be monitored closely. If there is no improvement, the hematocrit must be measured. If thehematocrit is still high, a second bolus of fluids should be given. In a patient with shock refractory to treatment, a hematocritthat is lower than the initial reference hematocrit is indicative of bleeding. In this instance, a blood transfusion is neededimmediately (WHO, TDR, 2009).Immunization:In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was registered in severalcountries for use in individuals 9-45 years of age living in endemic areas. WHO recommends that countries should considerintroduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological dataindicate a high burden of disease. Other tetravalent live-attenuated vaccines are under development in phase III clinicaltrials, and other vaccine candidates (based on subunit, DNA and purified inactivated virus platforms) are at earlier stages ofclinical development. WHO provides technical advice and guidance to countries and private partners to support vaccineresearch and evaluation.
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