Dengue virus | |
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A TEM micrograph showing dengue virus virions (the cluster of dark dots near the center) | |
Virus classification | |
(unranked): | Virus |
Realm: | Riboviria |
Kingdom: | Orthornavirae |
Phylum: | Kitrinoviricota |
Class: | Flasuviricetes |
Order: | Amarillovirales |
Family: | Flaviviridae |
Genus: | Flavivirus |
Species: | Dengue virus |
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]
Based on the analysis of the envelope protein, at least three genotypes (1 to 3) are known. In 2013, a fourth serotype was reported. [3] A single report of a fifth serotype DEN-5 in 2015 [10] has not been replicated or further reported on. [5] The rate of nucleotide substitution for this virus has been estimated to be 6.5×10−4 per nucleotide per year, a rate similar to other RNA viruses. The American African genotype has been estimated to have evolved between 1907 and 1949. This period includes World War I and World War II, which were associated with considerable movement of populations and environmental disturbance, factors known to promote the evolution of new vector-borne viral species.[ citation needed ]
A Bayesian analysis of all four serotypes estimated that their most recent common ancestor existed about 340 AD (95% confidence interval: 280 BC–850 AD). [11]
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 genome is about 11000 bases of positive-sense, single-stranded RNA (ssRNA) that codes for three structural proteins (capsid protein C, membrane protein M, envelope protein E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). [4] It also includes short noncoding regions on both the 5' and 3' ends. [1] [22]
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]
The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulfide bonds. [24]
The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E and M proteins. The immature virion starts out with the E and prM proteins forming 90 heterodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the Golgi apparatus. As the virion passes through the trans-Golgi network, it is exposed to low pH. This acidic environment causes a conformational change in the E protein, which disassociates it from the prM protein and causes it to form E homodimers, which lie flat against the viral surface, giving the maturing virion a smooth appearance. During this maturation, pr peptide is cleaved from the M peptide by the host protease, furin. The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell. [24]
The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1–180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135) is found between these two β-barrels, and activity is dependent on the presence of a 43 amino acid segment of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS2B residues before and after the cofactor region contain helical domains involved in membrane binding. The remaining NS3 residues (180–618) form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices makes up subdomains I and II, and subdomain III is composed of four α-helices surrounded by three shorter α-helices and two antiparallel β-strands. [24]
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]
The DENV NS5 protein is a 900-residue peptide with a methyltransferase domain at its N-terminal end (residues 1–296) and a RNA-dependent RNA polymerase (RdRp) at its C-terminal end (residues 320–900). The methyltransferase domain consists of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RdRp is similar to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides. [24]
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 ]
Common names for dengue fever include breakbone fever, vomiting and dandy fever; dengue hemorrhagic fever and dengue shock syndrome are the severe forms. [46] Dengue is found in tropical and subtropical climates worldwide, mostly in urban and semiurban areas. [47] People of all ages who are exposed to infected mosquitoes are at risk of developing dengue fever. The disease occurs most often during the rainy season in tropical countries in Southeast Asia, South Asia and South America, with high numbers of infected mosquitoes. [48] The virus is transmitted to humans through the bites of infected female mosquitoes, though humans are not capable of transmitting the disease and are not contagious. [47] [49] [48] The incubation period is 3 to 14 days, while the period of the illness is 3–7 days. [49] [50] Signs and symptoms may include severe headache; retro-orbital pain; muscle, joint, and bone pain; macular or maculopapular rash; and minor hemorrhagic manifestations, including petechiae, ecchymosis, purpura, epistaxis, bleeding gums, hematuria, or a positive tourniquet test result. [51] A recent systematic review and meta-analysis showed that allergic symptoms are one of the core symptoms that are highly associated with dengue severity. [52]
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]
In recent years, many studies have shown that flaviviruses, especially dengue virus, has the ability to inhibit the innate immune response during the infection. [55] [56] Indeed, dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response.[ citation needed ] These proteins act on two levels :
NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha & beta. In fact, as the activity of Tyk2 kinase decreases in association with dengue virus, so too does STAT 1 phosphorylation. [57] Furthermore, the innate immune system's response to the virus is further damped as expression of interferon-stimulating gene(s) (ISG) is restricted by the aforementioned 'NS4B' protein. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition. [58]
NS5 - the presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. [59] When NS5 is cleaved with NS4B by a protease (NS2B3), it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, an E3 ligase association with STAT2 occurs, and the E3 ligase targets STAT2 for the degradation. [60] [61]
NS2B3-b protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3. Cleavage of the NS2B3 precursor activates the protease complex. [62]
This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3. [63] The NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation. [64]
Dengue virus is transmitted by the mosquito species Aedes aegypti , which produces saliva that contains over 100 unique proteins, including the protein family D7. [65] Scientists used to believe that A. aegypti saliva, when being transmitted, actually enhanced dengue virus in the body. The mosquito's saliva was thought to make the virus spread faster due to the weakened immune response of its host. However, a current study has found that the protein D7 hinders the virus transmission into the host cells. [65]
The immune responses of antibodies that are trying to fight off the foreign virus actually increase transmission and make the infection worse. Levels of protein D7 are more prevalent in salivary glands of dengue-infected mosquitoes compared to those uninfected ones. [65] D7 is found in mosquito saliva and was thought to assist the process of blood feeding. Despite the prior assumptions, D7 can modulate the host cell and act against the virus to prevent viral infection. [65] Unfortunately, D7 proteins provoke immune responses, which raise anti-D7 antibody levels. These antibodies inhibit the function of D7 proteins, which enhance transmission of dengue virus[ citation needed ]. Although immune responses against D7 proteins might impair their antiviral activity, a study showed that non-DENV subjects have slightly higher anti-D7 IgG levels than infected ones, although it was not statistically significant. [66] Thus, more studies over D7 protein family are needed do elucidate its role on DENV infection and its applicability in medicine.
Two types of dengue vaccine have been approved and are commercially available. [67] [68] On 5 December 2022 the European Medicines Agency approved Qdenga, a live tetravalent attenuated vaccine for adults, adolescents and children from four years of age. [68] The 2016 vaccine Dengvaxia is only recommended in individuals who have been previously infected, or in populations with a high rate of prior infection by age nine. [69] [47] Dengvaxia has been approved in 11 countries (Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore). [70] [67] [71]
Several vaccines are under development by private and public researchers. [72] Developing a vaccine against the disease is challenging. With four different serotypes of the virus that can cause the disease, the vaccine must immunize against all four types to be effective. [3] Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock when infected with another serotype due to antibody-dependent enhancement. When infected with dengue virus, the immune system produces cross-reactive antibodies that provide immunity to that particular serotype. However, these antibodies are incapable of neutralizing other serotypes upon reinfection and actually increase viral replication. When macrophages consume the 'neutralized' virus, the virus is able to replicate within the macrophage, causing disease. These cross-reactive, ineffective antibodies ease access of the virus into macrophages, which induces more severe disease (dengue hemorrhagic fever, dengue shock syndrome). A common problem faced in dengue-endemic regions is when mothers become infected with dengue; after giving birth, offspring carry the immunity from their mother and are susceptible to hemorrhagic fever if infected with any of the other three serotypes. [73] One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started. [74]
In 2009, Sanofi-Pasteur started building a new facility in Neuville-sur-Saône' (fr), a suburb of Lyon (France). This unit produces four-serotype vaccine for phase III trials. In September 2014, the Sanofi-Pasteur CEO gave early results of the phase III trial efficacy study in Latin America. The efficacy per serotype (ST) varied widely, 42.3% for ST2, 50.3% for ST1, 74.0% for ST3, and 77.7% for ST4. The full analysis of data from the phase III Latin American-Caribbean study will be reviewed by external experts before being published in a peer-reviewed scientific journal. Primary results has to be presented at the American Society of Tropical Medicine and Hygiene Annual Meeting, held November 2–6, 2014, in New Orleans. [75]
In September 2012, one of the vaccines was reported to not have done well in clinical trials. [3]
In late 2015 and early 2016, the first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi-Pasteur, was registered in several countries for use in individuals 9–45 years of age living in endemic areas.[ citation needed ]
On May 1, 2019, the U.S. Food and Drug Administration announced the approval of Dengvaxia, the first vaccine for the prevention of dengue disease caused by all dengue virus serotypes in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands. [76]
There are no approved direct antiviral treatments for Dengue fever. Most antiviral drug research for Dengue infections has focussed on inhibition of the NS2B/NS3 protease or NS5 proteins. Reported protease inhibitor approaches have focussed mainly on targeted covalent inhibitors . [77] [78] One drug, Balapiravir, a repurposed hepatitis C NS5 polymerase inhibitor progressed to a Phase II clinical trial before being stopped due to lack of efficacy. [79] [80]
Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin 3 to 14 days after infection. These may include a high fever, headache, vomiting, muscle and joint pains, and a characteristic skin itching and skin rash. Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into a more severe dengue hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where dangerously low blood pressure occurs.
Rabies virus, scientific name Rabies lyssavirus, is a neurotropic virus that causes rabies in animals, including humans. Rabies transmission can occur through the saliva of animals and less commonly through contact with human saliva. Rabies lyssavirus, like many rhabdoviruses, has an extremely wide host range. In the wild it has been found infecting many mammalian species, while in the laboratory it has been found that birds can be infected, as well as cell cultures from mammals, birds, reptiles and insects. Rabies is reported in more than 150 countries and on all continents except Antarctica. The main burden of disease is reported in Asia and Africa, but some cases have been reported also in Europe in the past 10 years, especially in returning travellers.
Japanese encephalitis (JE) is an infection of the brain caused by the Japanese encephalitis virus (JEV). While most infections result in little or no symptoms, occasional inflammation of the brain occurs. In these cases, symptoms may include headache, vomiting, fever, confusion and seizures. This occurs about 5 to 15 days after infection.
Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses. VHFs may be caused by five distinct families of RNA viruses: the families Filoviridae, Flaviviridae, Rhabdoviridae, and several member families of the Bunyavirales order such as Arenaviridae, and Hantaviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica, while others, such as Ebola virus, can cause severe, life-threatening disease.
Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Flavivirus.
Original antigenic sin, also known as antigenic imprinting, the Hoskins effect, immunological imprinting, or primary addiction is the propensity of the immune system to preferentially use immunological memory based on a previous infection when a second slightly different version of that foreign pathogen is encountered. This leaves the immune system "trapped" by the first response it has made to each antigen, and unable to mount potentially more effective responses during subsequent infections. Antibodies or T-cells induced during infections with the first variant of the pathogen are subject to repertoire freeze, a form of original antigenic sin.
Pestivirus is a genus of viruses, in the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae and the family Suidae. There are 11 species in this genus. Diseases associated with this genus include: hemorrhagic syndromes, abortion, and fatal mucosal disease.
Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream. The name comes from combining the word "virus" with the Greek word for "blood" (haima). It usually lasts for 4 to 5 days in the primary condition.
A breakthrough infection is a case of illness in which a vaccinated individual becomes infected with the illness, because the vaccine has failed to provide complete immunity against the pathogen. Breakthrough infections have been identified in individuals immunized against a variety of diseases including mumps, varicella (Chickenpox), influenza, and COVID-19. The characteristics of the breakthrough infection are dependent on the virus itself. Often, infection of the vaccinated individual results in milder symptoms and shorter duration than if the infection were contracted naturally.
The Friend virus (FV) is a strain of murine leukemia virus identified by Charlotte Friend in 1957. The virus infects adult immunocompetent mice and is a well-established model for studying genetic resistance to infection by an immunosuppressive retrovirus. The Friend virus has been used for both immunotherapy and vaccines. It is a member of the retroviridae group of viruses, with its nucleic acid being ssRNA.
Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV virus and Dengue virus and is monitored for in vaccine development.
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.
RIG-I-like receptors are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system. RIG-I is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 and LGP2, this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection. The RLR receptors provide frontline defence against viral infections in most tissues.
Flavivirin is an enzyme.
Entebbe bat virus is an infectious disease caused by a Flavivirus that is closely related to yellow fever.
West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. The virus is primarily transmitted by mosquitoes, mostly species of Culex. The primary hosts of WNV are birds, so that the virus remains within a "bird–mosquito–bird" transmission cycle. The virus is genetically related to the Japanese encephalitis family of viruses. Humans and horses both exhibit disease symptoms from the virus, and symptoms rarely occur in other animals.
Yokose virus (YOKV) is in the genus Flavivirus of the family Flaviviridae. Flaviviridae are often found in arthropods, such as mosquitoes and ticks, and may also infect humans. The genus Flavivirus includes over 50 known viruses, including Yellow Fever, West Nile Virus, Zika Virus, and Japanese Encephalitis. Yokose virus is a new member of the Flavivirus family that has only been identified in a few bat species. Bats have been associated with several emerging zoonotic diseases such as Ebola and SARS.
Sepik virus (SEPV) is an arthropod-borne virus (arbovirus) of the genus Flavivirus and family Flaviviridae. Flaviviridae is one of the most well characterized viral families, as it contains many well-known viruses that cause diseases that have become very prevalent in the world, like Dengue virus. The genus Flavivirus is one of the largest viral genera and encompasses over 50 viral species, including tick and mosquito borne viruses like Yellow fever virus and West Nile virus. Sepik virus is much less well known and has not been as well-classified as other viruses because it has not been known of for very long. Sepik virus was first isolated in 1966 from the mosquito Mansoniaseptempunctata, and it derives its name from the Sepik River area in Papua New Guinea, where it was first found. The geographic range of Sepik virus is limited to Papua New Guinea, due to its isolation.
Modoc virus (MODV) is a rodent-associated flavivirus. Small and enveloped, MODV contains positive single-stranded RNA. Taxonomically, MODV is part of the Flavivirus genus and Flaviviridae family. The Flavivirus genus includes nearly 80 viruses, both vector-borne and no known vector (NKV) species. Known flavivirus vector-borne viruses include Dengue virus, Yellow Fever virus, tick-borne encephalitis virus, and West Nile virus.
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