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REVIEW ARTICLE
Year : 2022 | Volume
: 59
| Issue : 2 | Page : 109-114
An overview of dengue viral infection circulating in Pakistan
Liaqat Ali1, Zakkia Gul2, Asiya Ijaz3, Nouman Khalid4, Falak Zeb5, Samia Afzal6, Anayat Ullah7, Fazli Subhan1, Saeed Ahmed1
1 Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
2 Department of Biotechnology and Genetic Engineering, Hazara University, Mansehra, Pakistan
3 Department of Zoology, University of Poonch Rawalakot, Pakistan
4 Department of Life Sciences, Abasyn University Islamabad Campus, Rawalpindi, Pakistan
5 Department of Human Nutrition and Dietetics, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
6 Division of Molecular Virology & Infectious Diseases, Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan
7 Multidisciplinary Department, National University of Medical Sciences, Rawalpindi, Pakistan
Correspondence Address:
Liaqat Ali
Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi
Pakistan
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/0972-9062.331412
Background & objectives: Dengue virus (DENV) is an RNA virus that infects approximately 2.5 billion people around the world. The incidence of dengue fever has rapidly increased at an alarming rate in the last few years and has affected thousands of people in Pakistan. This review explores the prevalence, serotypes and pathogenesis of dengue virus circulating in Pakistan.
Methods: A systematic review of observational studies published between 1994 and December 2019 was performed. All records of the confirmed outbreak of dengue fever in Pakistan were reviewed and articles containing no primary data were excluded.
Results: Four identified serotypes of dengue virus (DENV 1-4) circulate in different regions of the world causing epidemics. The most prevalent serotype, which is still epidemic and dominant in Pakistan, is DENV-2. Many factors like over-population, rapid urbanization, travelling, lack of vector control in dengue endemic areas and inadequate health-care are responsible of dynamic and huge raise of dengue in Pakistan.
Interpretation & conclusion: Currently there is no specific treatment for prevention of dengue virus. Recently some antiviral compounds were being tested to eradicate this disease. There is a need to develop an efficient and safe vaccine for all four serotypes to combat dengue viral infection globally and particularly in Pakistan.
Keywords: Dengue virus; Serotypes; Prevalence; Pathogenesis; Non-structural proteins
Dengue fever is a widely spread mosquito-borne disease. It is a major health problem in all the areas that at the Tropic of Cancer and Tropic of Capricorn and subtropical areas such as Vietnam, Taiwan and Mexican Plateau[1]. Dengue is a Spanish word which means “fastidious”. It originated from word “dinga” which means an evil of spirit and was first described in 1789[2]. The causative agent of dengue fever is the dengue virus that is an enveloped positive single stranded RNA virus which belongs to the genus flavivirus and family flaviviridae[3]. This family also includes hepatitis c virus, West Nile Virus and yellow fever virus. All these viruses are lethal and cause severe damage to human health[4].
The transmission of dengue virus is similar to malaria that is transmitted to human by bite of an infected female mosquito of the genus Aedes, mostly Aedes aegypti[2],[3]. Aedes aegypti is a day biting mosquito that was later found in tropical and subtropical areas[3]. It breeds in collected stagnant water and is a normal female mosquito that becomes infected by the dengue infection if the mosquito comes in contact with a person that is a carrier of dengue. The infected mosquito later can transmit virus to non-infected person. The incubation period for dengue virus is 8–10 days[5]. This fever represents a broad range of clinical symptoms such as mild fever to sever muscles ache and sore lymph[5]. Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are the severe forms of dengue infection that are collectively responsible for the higher rate of transmission and mortality around the world[3],[6]. Severe headache, muscles and joints pain, rash, nausea, vomiting are the symptoms of dengue fever while DHF are characterized by high body temperature, hemorrhagic bleeding, hepatomegaly, and often circulatory disturbance and shock[3]. Dengue is the major cause of people getting hospitalized, and it is estimated that 500,000 people infected with severe dengue require hospitalization in which the ratio of children is dominant. The rate of mortality is 2.5% per annum[7].
The first wave of major epidemics of an illness caused by dengue was thought to be possibly occurred in three continents viz. Asia, Africa, and North America in early 1780s[8]. The similar illness had a wide geographic distribution before the 18th century, when the first known pandemic of dengue-like illness began with severe consequences. It is uncertain whether the epidemics in Batavia (Jakarta), Indonesia, and Cairo, Egypt, in 1779 were dengue[8], but it is quite likely that the Philadelphia epidemic of 1780 was dengue because all the symptoms and conditions of disease matched the previous viral disorder[7]. Dengue virus is found to be an endemic in about 128 countries that constitute approximately 3.9 billion of the world population[9]. Dengue serotype 2 is the most prevalent circulating sero-type in Pakistan. The journey of DENV in Pakistan started in 1985, but the first outbreak was officially confirmed in 1994[10] and cases were on its peak in 2010 onward[11].
In 2017, the province of Khyber Pakhtunkhawa (KP) faced an epidemic of dengue, with 18856 cases and multiple deaths that were later attributed to a different lineage of dengue virus serotype 2 circulating in Pakistan[11]. This lineage entered Pakistan from China around 2016 and spread in 2017[12]. The total number of dengue cases in Pakistan in 2017, 2018, 2019, and 2020 were 22938, 3204, 24547 and 106 respectively[13]. Many factors are responsible for dynamic and huge raise of dengue in Pakistan including uncontrolled growth of urban population, rapid urbanization, lack of vector control in dengue endemic areas, increased air travel and inadequate public health care systems, hospitals settings, biodiversity and ecosystem[14],[15],[16].
Genomic organization
Dengue virus is a 50 nm enveloped virus with positive sense single stranded RNA that directly translates into protein[3]. It is composed of approximately 11 kilo-base pair (kbp) that encodes for 3411 amino acids polypeptide molecules, that give rise to structural proteins (membrane, envelope, and capsid)[12] which are responsible for the basic structure of virus. The non-structural proteins (NS5, NS4B, NS4A, NS3, NS2B, NS2A, NS 1) which are expressed inside the infected cells [Figure 1][17],[18].
Figure 1: Genomic organization of dengue virus (created in Bio Render)[17].Prevalence and dengue serotypes in Pakistan
Dengue fever has become one of the most widespread mosquito-borne disease worldwide. In the past five years, the incidence of dengue fever has increased 30 times[18]. Currently, it is an endemic disease in 128 countries (mostly developing countries) and it poses a risk to approximately 3.9 billion people every year[8],[11]. The most recent dengue fever distribution model estimates that there are 390 million dengue infections each year, of which 96 million occur significantly[19]. Seventy-five percent of the world’s burden of dengue fever is in Asia, especially in the Philippines, Indonesia and Thailand. The dengue seroprevalence rate in Bangladesh and in South Asia is lower than that in Southeast Asian countries[12]. Since 1994, Pakistan has been endemic to dengue fever and now dengue fever has become a public health problem in Pakistan[11]. Dengue fever cases have been reported from 1994–2019 [Table 1] but since 2006, Pakistan has faced the worst cases of dengue fever. The disease has affected thousands of people and hundreds of lives have been lost[11].
In Pakistan, the spread of the dengue fever epidemic involves many factors. The most important factor is the favorable country climate as it is considered as a heaven for mosquito’s reproduction and maturation[11]. Another factor is unregulated and unplanned urbanization, inadequate public health care systems, hospital settings, biodiversity and ecosystem, which provides a lush breeding ground for Aedes[16]. Other key factors for dengue outbreaks includes improper sanitation facilities, overpopulation, lack of fresh drinking water, improper mosquito control, air travel, poor socioeconomic status, lack of public health support, and lack of awareness of health effects[3],[16].
Serotypes of DENV
DENV is divided into four serotypes related to antigens but are genetically different. They are DENV- 1, DENV-2, DENV-3 and DENV-4[3]. The nucleotide sequences of these four DENV serotypes differ by 25–35 base pairs and each serotype has the ability to cause dengue fever. Among the four different serotypes DENV- 4 seems to be the most different serotype, followed by DENV-2 and DENV-1 and DENV-3 are more closely related as described earlier[11]. Infection with any serotype provides long-term immunity to specific serotypes but only provides limited temporary immunity to the other serotypes. Epidemiological studies have shown that secondary infections of different serotypes may lead to more severe dengue fever[14].
Pathogenesis of dengue virus
Any of the dengue viral serotype is responsible for the etiology of dengue. A person affected by one of the serotypes of dengue achieves protective immunity against that particular serotype only [Figure 2]A[17] but not against the other serotype. Infection caused by another serotype for the second time becomes more severe[32]. Fcγ receptors are expressed via a process called antibody dependent enhancement and, in this way, antibodies promote entry of dengue virus[19]. So, when a person gets infected with heterologous serotype, antibody dependent enhancement enhances the infection by antibodies that have been produced against the first serotype [Figure 2]B[17],[33]. The antibodies having less defending ability against DENV structural proteins generated during primary infection can enable Antibody-dependent enhancement (ADE) in vivo during secondary infection. However, severe disease caused by secondary dengue infection is only caused in 2%–4% of individuals[32].
Figure 2: Mechanism of dengue viral infection: A. with same serotypes and B. different serotypes (created in Bio Render)[17].The quality and quantity of pre-existing antibody in serum induced by B cell pool is believed to react against severity of dengue infection[34],[35]. Within the cells of mononuclear phagocytes lineage i.e., monocytes, macrophages and B cells, dengue virus replicates when enters into the body through the bite of an infected mosquito[19].
The forthcoming infection with another serotype can be caused if a new serotype gets attached to the cross- reactive non-neutralizing antibody, produced as a result of previous infection by enhancing the viral replication by up taking mononuclear phagocytes[19]. In a severe condition when viral load is increased, a huge immune response is produced which leads to the increased cytokine response and in response of this, micro vascular permeability is increased which is the severe condition in dengue causing leakage of fluid into pleural and peritoneal cavity[36]. Mast cells, dendritic cells and endothelial cells are mostly infected[37]. Seven to ten days incubation period is required for dengue infection[36]. Within the help of dengue virus immune complexes attachment of FcγR receptor on myeloid or mast cell regulates in the host immunity and disease pathogenesis by enhancing the IL- 10 production, skewing the degranulation of vasoactive molecules to enhance the capillary leakage[34],[35]. In the secondary infection cross-reactive low affinity T-cells producing high levels of vasoactive cytokines that do not clear DENV infected cells completely[38] but studies show that CD 8+ cells can protect against severe dengue infection[39].
DENV, a virion composed of three structural proteins and seven non-structural proteins that is 10.7 kilo base capped RNA with spherical shape of 50 nm in diameter[3]. A protein having three-domain elongated structure (domain [D] I-III) is known as E protein, a class II viral membrane fusing protein, directs step in viral replication which have engagement with cellular attachment and entry factors, virion assembly and membrane fusion[35],[36]. The dengue virus binding factor includes glycosaminoglycan (heparin sulphate), C type lectins (DC- SIGN], mannose receptors and immunomodulatory proteins (TIM/ TAM receptors)[39]. A proper receptor for dengue virus attachment is not determined. Target cells of dengue virus are macrophages, dendritic cells, mast cells, monocytes, hepatocytes and endothelial cells[40]. Binding of virion is regulated by clathrin and leads to the trafficking of the virus particles to acidified late endosome and fusion of viral and host membrane is done by rearrangement of E-proteins[39],[40]. Then the viral genomic RNA is translated into a single polyprotein which is broken into the three structural proteins and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) by viral NS3 and host protease[38],[40]. Synthesis of Negative-strand viral RNA is done which further directs the synthesis of positive stranded RNA which is packaged into progeny virion and they form enveloped immature virion by budding into endoplasmic reticulum[40]. The E protein is organized during virion release and they exist as dimer of immature virions with PrM and are organized into the outer surface of virion as a hetrotrimeric spikes[40],[41]. This maturation occurs through action of furin protease in trans-golgi network and the virion secretion in extracellular spaces by exocytosis [Figure 3][17],[40].
LimitationsThis review presents comprehensive information and more detailed perceptions about dengue virus transmission in Pakistan. The limitations are due to the lack of adequate sharing of live data and information about health emergencies by the health care and management settings. Therefore, international research and diseases control funding agencies should support and collaborate with institutions in dengue endemic countries to scrutinize and control future pandemics in these areas.
ConclusionDengue fever is an endemic disease in 128 countries, particularly in developing countries like Pakistan, and it poses a risk to approximately 3.9 billion people each year. In this review, we propose the most prevalent serotype which is still epidemic and dominant in Pakistan since 1985/1994 is DENV-2. Like other viral infections the novel coronavirus pandemic also neutralized dengue infections in 2020. Many factors are responsible for dynamic and huge raise of dengue in Pakistan i.e., over population, rapid urbanization, travelling, lack of vector control in dengue endemic areas and inadequate health-care and management settings. Further research and investigation is required to developed antiviral therapy or vaccines that provide serotype-specific protective immunity.
Future direction and recommendation
The dengue viral infection is still a life-threatening problem worldwide and particularly in Pakistan. Climate change consideration is one of the factors to be considered for future strategies to manage dengue. The government diseases control team can take action to assure public health safety action to protect the public from dengue in the future. Detailed studies should be carried out in different dengue outbreak regions by providing proper healthcare settings for timely diagnosis and initial treatment on government level. The available tetravalent vaccine clinical trials should be started on emergency basis in epidemic regions. The new therapeutic and preventive approaches should be implemented to defeat dengue viral infections as recently described by Utarine and other researchers[41],[42].
Ethical statement: Not applicable
Conflict of interest: None
References
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