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The Journal of General Virology Dec 2019The assembly and secretion of flaviviruses are part of an elegantly regulated process. During maturation, the viral polyprotein undergoes several co- and...
The assembly and secretion of flaviviruses are part of an elegantly regulated process. During maturation, the viral polyprotein undergoes several co- and post-translational cleavages mediated by both viral and host proteases. Among these, sequential cleavage at the N and C termini of the hydrophobic capsid anchor (Ca) is crucial in deciding the fate of viral infection. Here, using a refined dengue pseudovirus production system, along with cleavage and furin inhibition assays, immunoblotting and secondary structure prediction analysis, we show that Ca plays a key role in the processing efficiency of dengue virus type 2 (DENV2) structural proteins and viral particle assembly. Replacement of the DENV2 Ca with the homologous regions from West nile or Zika viruses or, alternatively, increasing its length, improved cleavage and hence particle assembly. Further, we showed that substitution of the Ca conserved proline residue (P110) to alanine abolishes pseudovirus production, regardless of the Ca sequence length. Besides providing the results of a biochemical analysis of DENV2 structural polyprotein processing, this study also presents a system for efficient production of dengue pseudoviruses.
Topics: Amino Acid Sequence; Animals; Capsid; Capsid Proteins; Cell Line; Dengue; Dengue Virus; Humans; Protein Processing, Post-Translational; Protein Structure, Secondary; Proteolysis; Virus Assembly; Virus Replication; Zika Virus
PubMed: 31682219
DOI: 10.1099/jgv.0.001346 -
Current Topics in Medicinal Chemistry 2020Lethality due to dengue infection is a global threat. Nearly 400 million people are affected every year, which approximately costs 500 million dollars for surveillance... (Review)
Review
Lethality due to dengue infection is a global threat. Nearly 400 million people are affected every year, which approximately costs 500 million dollars for surveillance and vector control itself. Many investigations on the structure-function relationship of proteins expressed by the dengue virus are being made for more than a decade and had come up with many reports on small molecule drug discovery. In this review, we present a detailed note on viral proteins and their functions as well as the inhibitors discovered/designed so far using experimental and computational methods. Further, the phytoconstituents from medicinal plants, specifically the extract of the papaya leaves, neem and bael, which combat dengue infection via dengue protease, helicase, methyl transferase and polymerase are summarized.
Topics: Antiviral Agents; Dengue; Dengue Virus; Drug Discovery; Humans; Molecular Structure; Plant Extracts; Plant Leaves; Viral Proteins
PubMed: 32552652
DOI: 10.2174/1568026620666200618123026 -
Archives of Virology Dec 2019Dengue virus (DENV) is a mosquito-borne arbovirus that causes febrile illness and can lead to a potentially lethal disease. The mechanism of disease pathogenesis is not... (Review)
Review
Dengue virus (DENV) is a mosquito-borne arbovirus that causes febrile illness and can lead to a potentially lethal disease. The mechanism of disease pathogenesis is not completely understood, and there are currently no vaccines or therapeutic drugs available to protect against all four serotypes of DENV. Although many reasons have been suggested for the development of the disease, dengue studies have shown that, during DENV infection, there is an imbalance between oxidants and antioxidants that disrupts homeostasis. An increase in reactive oxygen species (ROS) levels triggers the sudden release of cytokines, which can lead to plasma leakage and other severe symptoms. In the present review, we give an overview of the oxidative stress response and its effect on the progression of dengue disease. We also discuss the role of oxidative-stress-associated molecules in disease prognostic and therapeutics.
Topics: Antioxidants; Cytokines; Dengue; Dengue Virus; Homeostasis; Humans; Oxidative Stress; Prognosis; Reactive Oxygen Species; Serogroup; Virulence
PubMed: 31531742
DOI: 10.1007/s00705-019-04406-7 -
Advances in Experimental Medicine and... 2018Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in... (Review)
Review
Signal-dependent movement of proteins into and out of the nucleus through the importin superfamily of transporters is central to the replication of many viruses in infected cells, including RNA viruses such as the flavivirus Dengue virus (DENV). DENV non-structural protein 5 (NS5) traffics into and out of the host cell nucleus/nucleolus, being observed in the nucleus, although to differing extents, very early in infection in the case of all 4 DENV serotypes; with results from both reverse genetics and inhibitor studies indicating that this trafficking is critical to DENV infection. Knowledge of the transporters and targeting signals responsible for nuclear trafficking of NS5 has enabled inhibitors of DENV NS5 nuclear import to be identified using a novel screening/counterscreen approach. N-(4-hydroxyphenyl) retinamide (4-HPR) is of particular interest as a specific, non-toxic inhibitor able to protect against infection by all four serotypes of DENV, as well as the severe, antibody-enhanced form of DENV infection, in a lethal mouse model. Since 4-HPR can also inhibit DENV-related flaviviruses of medical significance such as West Nile Virus and Zika virus, it is of great interest for future commercialisation. Targeting nucleocytoplasmic trafficking of flavivirus proteins promises to be a powerful strategy to counter flaviviruses, for which the development of protective vaccines has thus far proven problematic.
Topics: Active Transport, Cell Nucleus; Animals; Antiviral Agents; Dengue; Dengue Virus; Humans; Protein Transport; Viral Nonstructural Proteins
PubMed: 29845535
DOI: 10.1007/978-981-10-8727-1_15 -
Nature Communications Apr 2024Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced...
Dengue is the most prevalent mosquito-borne viral disease in humans, and cases are continuing to rise globally. In particular, islands in the Caribbean have experienced more frequent outbreaks, and all four dengue virus (DENV) serotypes have been reported in the region, leading to hyperendemicity and increased rates of severe disease. However, there is significant variability regarding virus surveillance and reporting between islands, making it difficult to obtain an accurate understanding of the epidemiological patterns in the Caribbean. To investigate this, we used travel surveillance and genomic epidemiology to reconstruct outbreak dynamics, DENV serotype turnover, and patterns of spread within the region from 2009-2022. We uncovered two recent DENV-3 introductions from Asia, one of which resulted in a large outbreak in Cuba, which was previously under-reported. We also show that while outbreaks can be synchronized between islands, they are often caused by different serotypes. Our study highlights the importance of surveillance of infected travelers to provide a snapshot of local introductions and transmission in areas with limited local surveillance and suggests that the recent DENV-3 introductions may pose a major public health threat in the region.
Topics: Dengue Virus; Dengue; Humans; Caribbean Region; Disease Outbreaks; Travel; Serogroup; Phylogeny; Epidemiological Monitoring
PubMed: 38664380
DOI: 10.1038/s41467-024-47774-8 -
Current Medicinal Chemistry 2024Viral infections continue to increase morbidity and mortality severely. The flavivirus genus has fifty different species, including the dengue, Zika, and West Nile... (Review)
Review
BACKGROUND
Viral infections continue to increase morbidity and mortality severely. The flavivirus genus has fifty different species, including the dengue, Zika, and West Nile viruses that can infect 40% of individuals globally, who reside in at least a hundred different countries. Dengue, one of the oldest and most dangerous human infections, was initially documented by the Chinese Medical Encyclopedia in the Jin period. It was referred to as "water poison," connected to flying insects, . DENV causes some medical expressions like dengue hemorrhagic fever, acute febrile illness, and dengue shock syndrome.
OBJECTIVE
According to the World Health Organization report of 2012, 2500 million people are in danger of contracting dengue fever worldwide. According to a recent study, 96 million of the 390 million dengue infections yearly show some clinical or subclinical severity. There is no antiviral drug or vaccine to treat this severe infection. It can be controlled by getting enough rest, drinking plenty of water, and using painkillers. The first dengue vaccine created by Sanofi, called Dengvaxia, was previously approved by the USFDA in 2019. All four serotypes of the DENV1-4 have shown re-infection in vaccine recipients. However, the usage of Dengvaxia has been constrained by its adverse effects.
CONCLUSION
Different classes of compounds have been reported against DENV, such as nitrogen-containing heterocycles (i.e., imidazole, pyridine, triazoles quinazolines, quinoline, and indole), oxygen-containing heterocycles (i.e., coumarins), and some are mixed heterocyclic compounds of S, N (thiazole, benzothiazine, and thiazolidinediones), and N, O (i.e., oxadiazole). There have been reports of computationally designed compounds to impede the molecular functions of specific structural and non-structural proteins as potential therapeutic targets. This review summarized the current progress in developing dengue protease inhibitors.
Topics: Dengue Virus; Humans; Antiviral Agents; Dengue; Protease Inhibitors; Animals; Drug Development
PubMed: 37723635
DOI: 10.2174/0929867331666230918110144 -
Protein Science : a Publication of the... Oct 2023The pupal cuticle protein from Aedes aegypti (AaPC) inhibits dengue virus (DENV) infection; however, the underlying mechanism of this inhibition remains unknown. Here,...
The pupal cuticle protein from Aedes aegypti (AaPC) inhibits dengue virus (DENV) infection; however, the underlying mechanism of this inhibition remains unknown. Here, we report that AaPC is an intrinsically disordered protein and interacts with domain I/II of the DENV envelope protein via residues Asp59, Asp61, Glu71, Asp73, Ser75, and Asp80. AaPC can directly bind to and cause the aggregation of DENV, which in turn blocks virus infection during the virus-cell fusion stage. AaPC may also influence viral recognition and attachment by interacting with human immune receptors DC-SIGN and CD4. These findings enhance our understanding of the role of AaPC in mitigating viral infection and suggest that AaPC is a potential target for developing inhibitors or antibodies to control dengue virus infection.
Topics: Animals; Humans; Dengue; Dengue Virus; Aedes; Pupa; Mosquito Vectors
PubMed: 37593853
DOI: 10.1002/pro.4761 -
Viruses Feb 2021Intrahost genetic diversity is thought to facilitate arbovirus adaptation to changing environments and hosts, and it might also be linked to viral pathogenesis. Dengue...
Intrahost genetic diversity is thought to facilitate arbovirus adaptation to changing environments and hosts, and it might also be linked to viral pathogenesis. Dengue virus serotype 2 (DENV-2) has circulated in Brazil since 1990 and is associated with severe disease and explosive outbreaks. Intending to shed light on the viral determinants for severe dengue pathogenesis, we sought to analyze the DENV-2 intrahost genetic diversity in 68 patient cases clinically classified as dengue fever ( = 31), dengue with warning signs ( = 19), and severe dengue ( = 18). Unlike previous DENV intrahost diversity studies whose approaches employed PCR, here we performed viral whole-genome deep sequencing from clinical samples with an amplicon-free approach, representing the real intrahost diversity scenario. Striking differences were detected in the viral population structure between the three clinical categories, which appear to be driven mainly by different infection times and selection pressures, rather than being linked with the clinical outcome itself. Diversity in the NS2B gene, however, showed to be constrained, irrespective of clinical outcome and infection time. Finally, 385 non-synonymous intrahost single-nucleotide variants located along the viral polyprotein, plus variants located in the untranslated regions, were consistently identified among the samples. Of them, 124 were exclusively or highly detected among cases with warning signs and among severe cases. However, there was no variant that by itself appeared to characterize the cases of greater severity, either due to its low intrahost frequency or the conservative effect on amino acid substitution. Although further studies are necessary to determine their real effect on viral proteins, this heightens the possibility of epistatic interactions. The present analysis represents an initial effort to correlate DENV-2 genetic diversity to its pathogenic potential and thus contribute to understanding the virus's dynamics within its human host.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brazil; Child; Child, Preschool; Dengue; Dengue Virus; Female; Genetic Variation; Genome, Viral; Humans; Infant; Male; Middle Aged; Phylogeny; Serogroup; Viral Nonstructural Proteins; Young Adult
PubMed: 33672226
DOI: 10.3390/v13020349 -
Annual Review of Virology Sep 2018Dengue virus (DENV) is the most prevalent medically important mosquito-borne virus in the world. Upon DENV infection of a host cell, DENV nonstructural protein 1 (NS1)... (Review)
Review
Dengue virus (DENV) is the most prevalent medically important mosquito-borne virus in the world. Upon DENV infection of a host cell, DENV nonstructural protein 1 (NS1) can be found intracellularly as a monomer, associated with the cell surface as a dimer, and secreted as a hexamer into the bloodstream. NS1 plays a variety of roles in the viral life cycle, particularly in RNA replication and immune evasion of the complement pathway. Over the past several years, key roles for NS1 in the pathogenesis of severe dengue disease have emerged, including direct action of the protein on the vascular endothelium and triggering release of vasoactive cytokines from immune cells, both of which result in endothelial hyperpermeability and vascular leak. Importantly, the adaptive immune response generates a robust response against NS1, and its potential contribution to dengue vaccines is also discussed.
Topics: Cytokines; Dengue; Dengue Vaccines; Dengue Virus; Endothelium, Vascular; Host-Pathogen Interactions; Immune Evasion; Permeability; RNA, Viral; Viral Nonstructural Proteins; Virus Replication
PubMed: 30044715
DOI: 10.1146/annurev-virology-101416-041848 -
Viruses Jul 2021Dengue virus (DENV) is one of the most prevalent neglected tropical diseases, with half of the world's population at risk of infection. In Nepal, DENV was first reported...
Dengue virus (DENV) is one of the most prevalent neglected tropical diseases, with half of the world's population at risk of infection. In Nepal, DENV was first reported in 2004, and its prevalence is increasing every year. The present study aimed to obtain and characterize the full-length genome sequence of DENV from the 2017 outbreak. Hospital-based surveillance was conducted in two provinces of Nepal during the outbreak. Acute-phase serum samples were collected from 141 clinically suspected dengue patients after the rainy season. By serological and molecular techniques, 37 (26.9%) and 49 (34.8%), respectively, were confirmed as dengue patients. The cosmopolitan genotype of DENV-2 was isolated from 27 laboratory-confirmed dengue patients. Genomic analysis showed many amino acid substitutions distributed mainly among the E, NS3, and NS5 genes. Phylogenetic analyses of the whole genome sequence revealed two clades (Asian and Indian) among DENV-2 isolates from Nepal. The DENV isolates from hilly and Terai areas were similar to Asian and Indian strains, respectively. Further genomic study on different DENV serotypes is warranted to understand DENV epidemics in Nepal, where there are limited scientific resources and infrastructure.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cross-Sectional Studies; Dengue; Dengue Virus; Disease Outbreaks; Female; Genotype; Humans; Infant; Male; Middle Aged; Nepal; Phylogeny; Serogroup; Whole Genome Sequencing; Young Adult
PubMed: 34452310
DOI: 10.3390/v13081444