Dengue Virus

The incidence of dengue has grown dramatically around the world in recent decades, with cases reported to WHO increased from 505 430 cases in 2000 to 5.2 million in 2019. A vast majority of cases are asymptomatic or mild and self-managed, and hence the actual numbers of dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses (1).

One modelling estimate indicates 390 million dengue virus infections per year of which 96 million manifest clinically (2). Another study on the prevalence of dengue estimates that 3.9 billion people are at risk of infection with dengue viruses.

Dengue Virus

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The largest number of dengue cases ever reported globally was in 2019. All regions were affected, and dengue transmission was recorded in Afghanistan for the first time. The American Region reported 3.1 million cases, with more than 25 000 classified as severe. A high number of cases were reported in Bangladesh (101 000), Malaysia (131 000) Philippines (420 000), Vietnam (320 000) in Asia.

The virus is transmitted to humans through the bites of infected female mosquitoes, primarily the Aedes aegypti mosquito. Other species within the Aedes genus can also act as vectors, but their contribution is secondary to Aedes aegypti.

Mosquitoes can become infected by people who are viremic with DENV. This can be someone who has a symptomatic dengue infection, someone who is yet to have a symptomatic infection (they are pre-symptomatic), but also people who show no signs of illness as well (they are asymptomatic).

The primary mode of transmission of DENV between humans involves mosquito vectors. There is evidence however, of the possibility of maternal transmission (from a pregnant mother to her baby). At the same time, vertical transmission rates appear low, with the risk of vertical transmission seemingly linked to the timing of the dengue infection during the pregnancy. When a mother does have a DENV infection when she is pregnant, babies may suffer from pre-term birth, low birthweight, and fetal distress.

Urbanization (especially unplanned), is associated with dengue transmission through multiple social and environmental factors: population density, human mobility, access to reliable water source, water storage practice etc.

So far one vaccine (Dengvaxia) has been approved and licensed in some countries. However, only persons with evidence of past dengue infection can be protected by this vaccine. Several additional dengue vaccine candidates are under evaluation.

Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus.[1][2] Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed,[3][4][5] all of which can cause the full spectrum of disease.[1] Nevertheless, scientists' understanding of dengue virus may be simplistic as, rather than distinct antigenic groups, a continuum appears to exist.[6] This same study identified 47 strains of dengue virus.[7] Additionally, coinfection with and lack of rapid tests for Zika virus and chikungunya complicate matters in real-world infections.[8]

Dengue virus has increased dramatically within the last 20 years, becoming one of the worst mosquito-borne human pathogens that tropical countries have to deal with. Current estimates indicate that as many as 390 million infections occur each year, and many dengue infections are increasingly understood to be asymptomatic or subclinical.[9]

Until a few hundred years ago, dengue virus was transmitted in sylvatic cycles in Africa, Southeast Asia and South Asia between mosquitoes of the genus Aedes and nonhuman primates, with rare emergences into human populations.[12][13] The global spread of dengue virus, however, has followed its emergence from sylvatic cycles and the primary lifecycle now exclusively involves transmission between humans and Aedes mosquitoes.[14] Vertical transmission from mosquito to mosquito has also been observed in some vector species.[15] Dogs have been found to be infected by the virus, but more research is needed to determine if dogs or other animals can serve as reservoirs or are just incidental hosts.[16]

Recent findings suggest that as the virus infects human cells, host homeostatic processes such as autophagy and ER stress response, not to mention apoptosis, are triggered depending on the infected cell type.[17] The activation of autophagy and ER stress during infection enhances virus reproduction.[18][19] Attempts to provide detailed summaries of the life cycle of dengue at the cellular level are published in review articles from different research groups.[20][21]

The DENV E (envelope) protein, found as a dimer on the surface of the mature viral particle, is important in the initial attachment of this particle to the host cell. Each E protein monomer comprises three ectodomains, ED1 to ED3, and a transmembrane segment. ED2 includes the dimerization interface, two glycosylation sites, and the peptide of fusion with the cellular membrane. ED3 is a continuous polypeptide segment; its fold is compact and immunoglobulin-like.[23][24] Dengue virus is transmitted by species of the mosquito genus Aedes. Several molecules that interact with the viral E protein (ICAM3-grabbing nonintegrin,[25] CD209,[26] Rab 5,[27] GRP 78,[28] and the mannose receptor[29]) have been shown to be important factors mediating attachment and viral entry.[24] The membrane form of ribosomal protein SA may also be involved in the attachment.[30] E protein is known to contain physicochemically conserved B cells and T cells specific epitopes, which can be exploited to design vaccine.[31] Recombinant domains of the E protein are used as well-defined antigens in the serological detection of antibodies directed against dengue virus and as immunogens in vaccine candidates.[32][33][34]

DENV NS4A is a nonstructural protein involved in altering cell membrane curvature[35] and induction of autophagy.[19] In addition to its membrane altering property, NS4A is a scaffold for the virus replication complex and undergoes oligomerization.[36] Mutations of NS4A that affect interaction with NS4B abolished or severely reduced virus replication indicating the importance of NS4A and its interaction with NS4B in dengue reproduction.[37]

Crystal structures of complexes between antibodies and either the ectodomain (sE) of the viral E protein or its domain 3 (ED3) have helped understand the molecular bases of the virus recognition and neutralization. Some of the epitopes are partially or totally inaccessible in the known structure of the mature virion. The corresponding antibodies are, therefore, assumed to bind to alternate or transitional conformations of the virus at 37 C.[citation needed]

Some people develop more severe forms of dengue, such as dengue hemorrhagic fever. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third, or fourth time. The previous antibodies to the old strain of dengue virus now interfere with the immune response to the current strain, paradoxically leading to more virus entry and uptake.[54] ff782bc1db