Research code: 1403-3-99-31404
Ethics code: 1403-3-99-31404
Clinical trials code: 1403-3-99-31404
Talieh Mostaghimi 
, Mobina Madihi , Zohre Khezeli , Niloofar Najafi , Mahshid Panahi , Gholamreza Hemmasi , Mohammad Hadi Karbalaie Niya *
, Mobina Madihi , Zohre Khezeli , Niloofar Najafi , Mahshid Panahi , Gholamreza Hemmasi , Mohammad Hadi Karbalaie Niya *
Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran , mohamad.karbalai@yahoo.com
Abstract: (69 Views)
Abstract
Dengue fever, a major infectious disease caused by arboviruses, has become a significant public health concern, particularly in tropical and subtropical regions. The disease is caused by the Dengue virus (DENV), which comprises four primary serotypes (DENV1-4) and a recently identified fifth serotype (DENV-5). The rapid spread of dengue is attributed to various factors including rapid population growth, unplanned urbanization, climate change, and increased travel, which have led to the virus's dissemination to new areas and among vulnerable human populations. This review article provides a comprehensive examination of the current status of DENV, including its genomic structure, pathogenesis mechanisms, life cycle, and methods for disease detection and control. The review emphasizes the importance of epidemiological monitoring in at-risk areas, particularly in countries like Iran where dengue is not yet widely prevalent. The analysis underscores the need for advancements in diagnostic technologies, the development of effective vaccines, and improved strategies for mosquito vector control. Furthermore, international collaboration and the use of novel technologies are essential for achieving the goal of dengue eradication by 2030. This article highlights the necessity of coordinated and comprehensive efforts to address this disease and mitigate its impact on public health and the global economy.
Keywords: Dengue; epidemiology; pathogenesis; diagnosis; treatment; disease control
Introduction
Dengue fever (DF) is one of the most widespread infectious diseases caused by arboviruses in the world, which can have fatal consequences and has become a serious public health concern worldwide, especially in tropical and subtropical regions (1, 2). In 1787, Benjamin Rush named the disease “bone-breaking fever” because of the myalgia and arthralgia symptoms seen in the Philadelphia epidemics of 1780 (3). Epidemics of dengue fever were recognized clinically in Asia, Africa, and North America in the 1780s (4). Approximately half of the world's population is at risk of dengue, and it is estimated that between 100 and 400 million infections occur annually (1). This disease is caused by dengue virus (DENV), which belongs to the flavivirus genus of the flaviviridae family and includes four distinct antigenic serotypes (DENV1-4), each of which is divided into different and genetically diverse genotypes. (4) Epidemiologically, including genetic diversity, transmission dynamics, and epidemic potential, all serotypes are nearly identical, except for DENV-4, which is genetically distinct (5). In addition to the four known DENV serotypes worldwide, a fifth serotype (DENV-5) was also identified from a suspected patient in Malaysia in 2007 using isolation and genetic sequence analysis and announced in 2013 (6).
The alarming rise and spread of the disease's epidemiology is mainly facilitated by rapid human population growth, rapid urbanization without adequate health infrastructure, deforestation, increased travel, and climate change. These factors have caused the virus to spread to new geographic areas where the vector mosquitoes Aedes aegypti and Aedes albopictus are involved in the transmission and circulation of the virus among large populations of immunologically naive human hosts. It is worth noting that these mosquito species are also carriers of other arboviruses such as chikungunya, Zika and yellow fever viruses (1).
Comprehensive and advanced studies that examine the current status of dengue virus and the dynamics of dengue fever are of great importance for the diagnosis and management of emerging cases of this disease in countries such as Iran, where dengue fever has not yet been widely raised as a serious public health problem. This review study analyzes the epidemiology, genomic structure, pathogenesis, life cycle of the virus, clinical symptoms and methods of diagnosis and control of dengue disease and examines its trend in Iran.
Materials and Methods
Search Strategy
The search for studies was based on the use of keywords derived from MeSH terms, and the selection of studies from databases was done independently using the referene management software (Endnote). In this study, several reputable databases such as PubMed, Web of Science ISI, Scopus, and Google Scholar were used to search for articles by considering related keywords such as "dengue fever, dengue virus, osteomalacia, Aedes mosquito, pathogenesis, epidemiology, and etc.".
Selection of Studies
The search was limited to original articles and abstracts of articles that investigated this viral disease. The review of articles was conducted according to the keywords in the article abstract, article topic, and article keywords. From all collected articles, information such as the author's name, year of publication, year of research, size of the study population, and geographical location of the research were extracted. The inclusion criteria for articles included: published articles, articles in English and Persian, and original articles, case-control or prevalence studies, and publication year from 1998 to 2024. The exclusion criteria for articles included: articles in languages other than English, and Presion and review articles, commentaries, and letters to the editor.
Data extraction
Data were extracted by two independent reviewers using standard forms to ensure accuracy and consistency in the results. These data included study characteristics, study population, virology of the agent, epidemiology, methods of diagnosis, prevention, control, and treatment.
Results and Discussion
Dengue virus structure and genome
Dengue virus is a spherical virion with a diameter of approximately 50 nm. The genome of this virus is a single-stranded, positive-sense RNA of 11 kb. The 5′ and 3′ ends of the dengue virus RNA genome contain untranslated regions (UTRs) that are essential for viral replication and translation and likely interact with associated cellular factors. The central region contains a large open reading frame (ORF) flanked by the 5′ and 3′ UTRs that encode a variety of proteins (Fig. 1A) (7). These proteins are divided into two main categories: structural proteins, which include the capsid proteins (C), premembrane protein (prM), and envelope protein (E), and nonstructural proteins, which are divided into NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5, which are involved in genome replication, virion assembly, and invasion of the innate immune response (8, 9).
In general, dengue virus has two distinct morphological forms: an intracellular immature form and a mature virion form. The mature virion is distinguished by the presence of two proteins, E and M, encoded by the virus in the membrane, which give it a relatively smooth surface. In contrast, the intracellular immature virion has an E protein and a premembrane protein (prM). During the maturation process, the prM protein is converted to the M protein. During this process, the immature virion changes its protein surface in an asymmetrical and prominent manner due to the acidification of the environment. However, sometimes semi-mature or immature forms may also be released from infected cells. (8, 9)
Dengue virus transmission
Dengue virus transmission is mainly based on infection in Aedes mosquitoes, especially Aedes aegypti and Aedes albopictus. Aedes mosquitoes are members of the Colicidae family, and arboviruses are transmitted mainly by Aedes aegypti mosquitoes, with Aedes albopictus as a secondary vector in some areas. These mosquitoes breed in small bodies of stagnant water, especially in water storage containers near residential buildings. Aedes aegypti mosquitoes and their larvae are commonly found indoors, especially in urban areas, while Aedes albopictus mosquitoes are more likely to be found outdoors in rural and suburban areas. (11) Aedes aegypti and Aedes albopictus mosquitoes are black in color and can be identified by white stripes on the upper part of their thorax. Aedes aegypti has two straight lines with curved lines, while Aedes albopictus has a broad stripe running down the center of the thorax. After mating, adult female mosquitoes lay 60 to 100 eggs in artificial and natural environments by feeding on blood and typically live for 20 to 30 days. These mosquitoes bite during the day, especially in the early morning and before dusk (12, 13). As shown in Figure 2, when a female Aedes mosquito bites an individual infected with dengue virus, it receives the virus along with the infected individual’s blood. The virus then replicates in the mosquito’s midgut and spreads to other tissues, including the salivary glands. This process, known as the external incubation period, lasts about 8 to 10 days. When the infected mosquito bites another individual, the virus is transferred through its saliva and infects the new host. The internal incubation period of the virus in humans is 4–7 days. After entering the human body, dengue virus infects and replicates in various cells, including monocytes, macrophages, and dendritic cells. The virus then spreads to the lymph nodes and enters the bloodstream, leading to viremia (13, 14). In addition to direct transmission through mosquito bites, dengue virus can also be transmitted by other routes. These routes include vertical transmission from mother mosquitoes to eggs, transmission through blood transfusions and organ transplantation, and perinatal transmission from mother to fetus. These different modes of transmission indicate that controlling the spread of dengue virus requires attention to multiple factors, including mosquito population control and prevention of human-to-human transmission. (15, 16)
Dengue Virus Pathogenesis
The pathogenesis of dengue virus infection involves several steps, from virus entry into the body to the development of immune responses and the possible development of severe disease.
Dengue fever, a major infectious disease caused by arboviruses, has become a significant public health concern, particularly in tropical and subtropical regions. The disease is caused by the Dengue virus (DENV), which comprises four primary serotypes (DENV1-4) and a recently identified fifth serotype (DENV-5). The rapid spread of dengue is attributed to various factors including rapid population growth, unplanned urbanization, climate change, and increased travel, which have led to the virus's dissemination to new areas and among vulnerable human populations. This review article provides a comprehensive examination of the current status of DENV, including its genomic structure, pathogenesis mechanisms, life cycle, and methods for disease detection and control. The review emphasizes the importance of epidemiological monitoring in at-risk areas, particularly in countries like Iran where dengue is not yet widely prevalent. The analysis underscores the need for advancements in diagnostic technologies, the development of effective vaccines, and improved strategies for mosquito vector control. Furthermore, international collaboration and the use of novel technologies are essential for achieving the goal of dengue eradication by 2030. This article highlights the necessity of coordinated and comprehensive efforts to address this disease and mitigate its impact on public health and the global economy.
Keywords: Dengue; epidemiology; pathogenesis; diagnosis; treatment; disease control
Introduction
Dengue fever (DF) is one of the most widespread infectious diseases caused by arboviruses in the world, which can have fatal consequences and has become a serious public health concern worldwide, especially in tropical and subtropical regions (1, 2). In 1787, Benjamin Rush named the disease “bone-breaking fever” because of the myalgia and arthralgia symptoms seen in the Philadelphia epidemics of 1780 (3). Epidemics of dengue fever were recognized clinically in Asia, Africa, and North America in the 1780s (4). Approximately half of the world's population is at risk of dengue, and it is estimated that between 100 and 400 million infections occur annually (1). This disease is caused by dengue virus (DENV), which belongs to the flavivirus genus of the flaviviridae family and includes four distinct antigenic serotypes (DENV1-4), each of which is divided into different and genetically diverse genotypes. (4) Epidemiologically, including genetic diversity, transmission dynamics, and epidemic potential, all serotypes are nearly identical, except for DENV-4, which is genetically distinct (5). In addition to the four known DENV serotypes worldwide, a fifth serotype (DENV-5) was also identified from a suspected patient in Malaysia in 2007 using isolation and genetic sequence analysis and announced in 2013 (6).
The alarming rise and spread of the disease's epidemiology is mainly facilitated by rapid human population growth, rapid urbanization without adequate health infrastructure, deforestation, increased travel, and climate change. These factors have caused the virus to spread to new geographic areas where the vector mosquitoes Aedes aegypti and Aedes albopictus are involved in the transmission and circulation of the virus among large populations of immunologically naive human hosts. It is worth noting that these mosquito species are also carriers of other arboviruses such as chikungunya, Zika and yellow fever viruses (1).
Comprehensive and advanced studies that examine the current status of dengue virus and the dynamics of dengue fever are of great importance for the diagnosis and management of emerging cases of this disease in countries such as Iran, where dengue fever has not yet been widely raised as a serious public health problem. This review study analyzes the epidemiology, genomic structure, pathogenesis, life cycle of the virus, clinical symptoms and methods of diagnosis and control of dengue disease and examines its trend in Iran.
Materials and Methods
Search Strategy
The search for studies was based on the use of keywords derived from MeSH terms, and the selection of studies from databases was done independently using the referene management software (Endnote). In this study, several reputable databases such as PubMed, Web of Science ISI, Scopus, and Google Scholar were used to search for articles by considering related keywords such as "dengue fever, dengue virus, osteomalacia, Aedes mosquito, pathogenesis, epidemiology, and etc.".
Selection of Studies
The search was limited to original articles and abstracts of articles that investigated this viral disease. The review of articles was conducted according to the keywords in the article abstract, article topic, and article keywords. From all collected articles, information such as the author's name, year of publication, year of research, size of the study population, and geographical location of the research were extracted. The inclusion criteria for articles included: published articles, articles in English and Persian, and original articles, case-control or prevalence studies, and publication year from 1998 to 2024. The exclusion criteria for articles included: articles in languages other than English, and Presion and review articles, commentaries, and letters to the editor.
Data extraction
Data were extracted by two independent reviewers using standard forms to ensure accuracy and consistency in the results. These data included study characteristics, study population, virology of the agent, epidemiology, methods of diagnosis, prevention, control, and treatment.
Results and Discussion
Dengue virus structure and genome
Dengue virus is a spherical virion with a diameter of approximately 50 nm. The genome of this virus is a single-stranded, positive-sense RNA of 11 kb. The 5′ and 3′ ends of the dengue virus RNA genome contain untranslated regions (UTRs) that are essential for viral replication and translation and likely interact with associated cellular factors. The central region contains a large open reading frame (ORF) flanked by the 5′ and 3′ UTRs that encode a variety of proteins (Fig. 1A) (7). These proteins are divided into two main categories: structural proteins, which include the capsid proteins (C), premembrane protein (prM), and envelope protein (E), and nonstructural proteins, which are divided into NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5, which are involved in genome replication, virion assembly, and invasion of the innate immune response (8, 9).
In general, dengue virus has two distinct morphological forms: an intracellular immature form and a mature virion form. The mature virion is distinguished by the presence of two proteins, E and M, encoded by the virus in the membrane, which give it a relatively smooth surface. In contrast, the intracellular immature virion has an E protein and a premembrane protein (prM). During the maturation process, the prM protein is converted to the M protein. During this process, the immature virion changes its protein surface in an asymmetrical and prominent manner due to the acidification of the environment. However, sometimes semi-mature or immature forms may also be released from infected cells. (8, 9)
Dengue virus transmission
Dengue virus transmission is mainly based on infection in Aedes mosquitoes, especially Aedes aegypti and Aedes albopictus. Aedes mosquitoes are members of the Colicidae family, and arboviruses are transmitted mainly by Aedes aegypti mosquitoes, with Aedes albopictus as a secondary vector in some areas. These mosquitoes breed in small bodies of stagnant water, especially in water storage containers near residential buildings. Aedes aegypti mosquitoes and their larvae are commonly found indoors, especially in urban areas, while Aedes albopictus mosquitoes are more likely to be found outdoors in rural and suburban areas. (11) Aedes aegypti and Aedes albopictus mosquitoes are black in color and can be identified by white stripes on the upper part of their thorax. Aedes aegypti has two straight lines with curved lines, while Aedes albopictus has a broad stripe running down the center of the thorax. After mating, adult female mosquitoes lay 60 to 100 eggs in artificial and natural environments by feeding on blood and typically live for 20 to 30 days. These mosquitoes bite during the day, especially in the early morning and before dusk (12, 13). As shown in Figure 2, when a female Aedes mosquito bites an individual infected with dengue virus, it receives the virus along with the infected individual’s blood. The virus then replicates in the mosquito’s midgut and spreads to other tissues, including the salivary glands. This process, known as the external incubation period, lasts about 8 to 10 days. When the infected mosquito bites another individual, the virus is transferred through its saliva and infects the new host. The internal incubation period of the virus in humans is 4–7 days. After entering the human body, dengue virus infects and replicates in various cells, including monocytes, macrophages, and dendritic cells. The virus then spreads to the lymph nodes and enters the bloodstream, leading to viremia (13, 14). In addition to direct transmission through mosquito bites, dengue virus can also be transmitted by other routes. These routes include vertical transmission from mother mosquitoes to eggs, transmission through blood transfusions and organ transplantation, and perinatal transmission from mother to fetus. These different modes of transmission indicate that controlling the spread of dengue virus requires attention to multiple factors, including mosquito population control and prevention of human-to-human transmission. (15, 16)
Dengue Virus Pathogenesis
The pathogenesis of dengue virus infection involves several steps, from virus entry into the body to the development of immune responses and the possible development of severe disease.
Type of Study: review article |
Subject:
Infectious Disease
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