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Viruses Jan 2022Flaviviruses such as dengue virus (DENV) and Zika virus (ZIKV) have evolved sophisticated mechanisms to suppress the host immune system. For instance, flavivirus...
Flaviviruses such as dengue virus (DENV) and Zika virus (ZIKV) have evolved sophisticated mechanisms to suppress the host immune system. For instance, flavivirus infections were found to sabotage peroxisomes, organelles with an important role in innate immunity. The current model suggests that the capsid (C) proteins of DENV and ZIKV downregulate peroxisomes, ultimately resulting in reduced production of interferons by interacting with the host protein PEX19, a crucial chaperone in peroxisomal biogenesis. Here, we aimed to explore the importance of peroxisomes and the role of C interaction with PEX19 in the flavivirus life cycle. By infecting cells lacking peroxisomes we show that this organelle is required for optimal DENV replication. Moreover, we demonstrate that DENV and ZIKV C bind PEX19 through a conserved PEX19-binding motif, which is also commonly found in cellular peroxisomal membrane proteins (PMPs). However, in contrast to PMPs, this interaction does not result in the targeting of C to peroxisomes. Furthermore, we show that the presence of C results in peroxisome loss due to impaired peroxisomal biogenesis, which appears to occur by a PEX19-independent mechanism. Hence, these findings challenge the current model of how flavivirus C might downregulate peroxisomal abundance and suggest a yet unknown role of peroxisomes in flavivirus biology.
Topics: Animals; Capsid Proteins; Cell Line; Dengue Virus; Humans; Membrane Proteins; Organelle Biogenesis; Peroxisomes; Protein Interaction Domains and Motifs; Virus Replication; Zika Virus
PubMed: 35215846
DOI: 10.3390/v14020253 -
Molecules (Basel, Switzerland) Sep 2021Mosquito transmitted viruses, particularly those of the genus , are a significant healthcare burden worldwide, especially in tropical and sub-tropical areas. However,...
Mosquito transmitted viruses, particularly those of the genus , are a significant healthcare burden worldwide, especially in tropical and sub-tropical areas. However, effective medicines for these viral infections remains lacking. Berberine (BBR) is an alkaloid found in some plants used in traditional medicines in Southeast Asia and elsewhere, and BBR has been shown to possess anti-viral activities. During a screen for potential application to mosquito transmitted viruses, BBR was shown to have virucidal activity against dengue virus (DENV; IC 42.87 µM) as well as against Zika virus (IC 11.42 µM) and chikungunya virus (IC 14.21 µM). BBR was shown to have cellular effects that lead to an increase in cellular DENV E protein without a concomitant effect on DENV nonstructural proteins, suggesting an effect on viral particle formation or egress. While BBR was shown to have an effect of ERK1/2 activation this did not result in defects in viral egress mechanisms. The primary effect of BBR on viral production was likely to be through BBR acting through AMPK activation and disruption of lipid metabolism. Combined these results suggest that BBR has a dual effect on DENV infection, and BBR may have the potential for development as an anti-DENV antiviral.
Topics: Animals; Antiviral Agents; Berberine; Chlorocebus aethiops; Dengue Virus; Vero Cells; Virus Replication
PubMed: 34576974
DOI: 10.3390/molecules26185501 -
Communications Biology May 2021Dengue virus (DENV) is spread from human to human through the bite of the female Aedes aegypti mosquito and leads to about 100 million clinical infections yearly....
Dengue virus (DENV) is spread from human to human through the bite of the female Aedes aegypti mosquito and leads to about 100 million clinical infections yearly. Treatment options and vaccine availability for DENV are limited. Defective interfering particles (DIPs) are considered a promising antiviral approach but infectious virus contamination has limited their development. Here, a DENV-derived DIP production cell line was developed that continuously produced DENV-free DIPs. The DIPs contained and could deliver to cells a DENV serotype 2 subgenomic defective-interfering RNA, which was originally discovered in DENV infected patients. The DIPs released into cell culture supernatant were purified and could potently inhibit replication of all DENV serotypes in cells. Antiviral therapeutics are limited for many viral infection. The DIP system described could be re-purposed to make antiviral DIPs for many other RNA viruses such as SARS-CoV-2, yellow fever, West Nile and Zika viruses.
Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; Defective Viruses; Dengue; Dengue Vaccines; Dengue Virus; Genes, Reporter; HEK293 Cells; Host-Pathogen Interactions; Humans; Luminescent Proteins; RNA, Viral; Vero Cells; Viral Load; Virus Replication
PubMed: 33976375
DOI: 10.1038/s42003-021-02064-7 -
Current Opinion in Virology Aug 2020Dengue virus (DENV) causes the most prevalent arbovirus illness worldwide and is responsible for many debilitating epidemics. The four circulating DENV serotypes infect... (Review)
Review
Dengue virus (DENV) causes the most prevalent arbovirus illness worldwide and is responsible for many debilitating epidemics. The four circulating DENV serotypes infect humans and can cause asymptomatic, mild, moderate, or severe Dengue. Because of the global morbidity and mortality due to Dengue, deployment of a safe and effective tetravalent vaccine has been a high priority, and to date, a partially realized goal. The study of pathogenesis and development of DENV therapeutics and vaccines has been limited by few animal models that recapitulate key features of human disease. Over the past two decades, mouse models of DENV infection have evolved with increasing success. Here, we review the utilization and limitations of mice for studying DENV pathogenesis and evaluating countermeasures.
Topics: Animals; Dengue; Dengue Vaccines; Dengue Virus; Disease Models, Animal; Humans; Mice; Virulence
PubMed: 32950933
DOI: 10.1016/j.coviro.2020.09.001 -
Archives of Virology Apr 2021Dengue virus (DV) is a mosquito-borne virus that is endemic to many tropical and subtropical areas. Recently, the annual incidence of DV infection has increased...
Dengue virus (DV) is a mosquito-borne virus that is endemic to many tropical and subtropical areas. Recently, the annual incidence of DV infection has increased worldwide, including in Korea, due to global warming and increased global travel. We therefore sought to characterize the molecular and evolutionary features of DV-1 and DV-4 isolated from Korean overseas travelers. We used phylogenetic analysis based on the full coding region to classify isolates of DV-1 in Korea into genotype I (43251, KP406802), genotype IV (KP406803), and genotype V (KP406801). In addition, we found that strains of DV-4 belonged to genotype I (KP406806) and genotype II (43257). Evidence of positive selection in DV-1 strains was identified in the C, prM, NS2A, and NS5 proteins, whereas DV-4 showed positive selection only in the non-structural proteins NS2A, NS3, and NS5. The substitution rates per site per year were 5.58 × 10 and 6.72 × 10 for DV-1 and DV-4, respectively, and the time of the most recent common ancestor was determined using the Bayesian skyline coalescent method. In this study, the molecular, phylogenetic, and evolutionary characteristics of Korean DV-1 and DV-4 isolates were evaluated for the first time.
Topics: Amino Acid Sequence; Amino Acid Substitution; Base Sequence; Dengue; Dengue Virus; Evolution, Molecular; Genotype; Humans; Phylogeny; RNA, Viral; Republic of Korea; Selection, Genetic; Serogroup; Travel; Viral Proteins
PubMed: 33575893
DOI: 10.1007/s00705-021-04973-8 -
ELife Feb 2018Dengue and Zika viral infections affect millions of people annually and can be complicated by hemorrhage and shock or neurological manifestations, respectively. However,...
Dengue and Zika viral infections affect millions of people annually and can be complicated by hemorrhage and shock or neurological manifestations, respectively. However, a thorough understanding of the host response to these viruses is lacking, partly because conventional approaches ignore heterogeneity in virus abundance across cells. We present viscRNA-Seq (virus-inclusive single cell RNA-Seq), an approach to probe the host transcriptome together with intracellular viral RNA at the single cell level. We applied viscRNA-Seq to monitor dengue and Zika virus infection in cultured cells and discovered extreme heterogeneity in virus abundance. We exploited this variation to identify host factors that show complex dynamics and a high degree of specificity for either virus, including proteins involved in the endoplasmic reticulum translocon, signal peptide processing, and membrane trafficking. We validated the viscRNA-Seq hits and discovered novel proviral and antiviral factors. viscRNA-Seq is a powerful approach to assess the genome-wide virus-host dynamics at single cell level.
Topics: Cell Line; Dengue Virus; Gene Expression Profiling; Hepatocytes; Host-Pathogen Interactions; Humans; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic; Zika Virus
PubMed: 29451494
DOI: 10.7554/eLife.32942 -
PLoS Neglected Tropical Diseases 2014This literature analysis describes the available dengue epidemiology data in the Philippines between 2000 and 2011. Of 253 relevant data sources identified, 34,... (Review)
Review
This literature analysis describes the available dengue epidemiology data in the Philippines between 2000 and 2011. Of 253 relevant data sources identified, 34, including additional epidemiology data provided by the National Epidemiology Center, Department of Health, Philippines, were reviewed. There were 14 publications in peer reviewed journals, and 17 surveillance reports/sources, which provided variable information from the passive reporting system and show broad trends in dengue incidence, including age group predominance and disease severity. The peer reviewed studies focused on clinical severity of cases, some revealed data on circulating serotypes and genotypes and on the seroepidemiology of dengue including incidence rates for infection and apparent disease. Gaps in the data were identified, and include the absence incidence rates stratified by age, dengue serotype and genotype distribution, disease severity data, sex distribution data, and seroprevalence data.
Topics: Age Distribution; Dengue; Dengue Virus; Environment; Genotype; Humans; Incidence; Philippines; Seasons; Seroepidemiologic Studies; Serogroup; Sex Distribution
PubMed: 25375119
DOI: 10.1371/journal.pntd.0003027 -
Viruses Sep 2021Dengue is the most significant arbovirus worldwide and a public health threat to non-endemic areas in which vectors are present. Autochthonous dengue transmission has...
Dengue is the most significant arbovirus worldwide and a public health threat to non-endemic areas in which vectors are present. Autochthonous dengue transmission has been reported in several European countries in the last decade. Infected travelers from endemic regions arriving to areas colonized by in Europe need to be monitored in surveillance and control programs. We aimed to perform molecular characterization of RT-PCR-positive dengue cases detected in Catalonia, northeastern Spain, from 2013 to 2018. The basic demographic information and the geographical regions of importation were also analyzed. One-hundred four dengue cases were studied (103 imported infections and the first autochthonous case in our region). The dengue virus strains detected were serotyped and genotyped using molecular methods, and phylogenetic analyses were conducted. All four dengue serotypes were detected in travelers, including up to 10 different genotypes, reflecting the global circulation of dengue in endemic areas. The primary travel-related case of the 2018 autochthonous transmission was not identified, but the molecular analysis revealed dengue serotype 1, genotype I of Asian origin. Our results highlight the diversity of imported dengue virus strains and the role of molecular epidemiology in supporting arbovirus surveillance programs.
Topics: Adult; Aedes; Aged; Animals; Communicable Diseases, Imported; Dengue; Dengue Virus; Europe; Female; Genotype; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Molecular Epidemiology; Phylogeny; Public Health; Spain; Young Adult
PubMed: 34696340
DOI: 10.3390/v13101910 -
Current Opinion in Virology Aug 2020The first licensed dengue vaccine led to considerable controversy, and to date, no dengue vaccine is in widespread use. All three leading dengue vaccine candidates are... (Review)
Review
The first licensed dengue vaccine led to considerable controversy, and to date, no dengue vaccine is in widespread use. All three leading dengue vaccine candidates are live attenuated vaccines, with the main difference between them being the type of backbone and the extent of chimerization. While CYD-TDV (the first licensed dengue vaccine) does not include non-structural proteins of dengue, TAK-003 contains the dengue virus serotype 2 backbone, and the Butantan/Merck vaccine contains three full-genomes of the four dengue virus serotypes. While dengue-primed individuals can already benefit from vaccination against all four serotypes with the first licensed dengue vaccine CYD-TDV, the need for dengue-naive population has not yet been met. To improve tetravalent protection, sequential vaccination should be considered in addition to a heterologous prime-boost approach.
Topics: Animals; Dengue; Dengue Vaccines; Dengue Virus; Drug Development; Humans
PubMed: 33086187
DOI: 10.1016/j.coviro.2020.09.004 -
PLoS Neglected Tropical Diseases Jan 2017Dengue, the predominant arthropod-borne viral disease affecting humans, is caused by one of four distinct serotypes (DENV-1, -2, -3 or -4). A literature analysis and... (Review)
Review
Dengue, the predominant arthropod-borne viral disease affecting humans, is caused by one of four distinct serotypes (DENV-1, -2, -3 or -4). A literature analysis and review was undertaken to describe the molecular epidemiological trends in dengue disease and the knowledge generated in specific molecular topics in Latin America, including the Caribbean islands, from 2000 to 2013 in the context of regional trends in order to identify gaps in molecular epidemiological knowledge and future research needs. Searches of literature published between 1 January 2000 and 30 November 2013 were conducted using specific search strategies for each electronic database that was reviewed. A total of 396 relevant citations were identified, 57 of which fulfilled the inclusion criteria. All four dengue virus serotypes were present and co-circulated in many countries over the review period (with the predominance of individual serotypes varying by country and year). The number of countries in which more than one serotype circulated steadily increased during the period under review. Molecular epidemiology data were found for Argentina, Bolivia, Brazil, the Caribbean region, Colombia, Ecuador, Mexico and Central America, Paraguay, Peru and Venezuela. Distinct lineages with different dynamics were found in each country, with co-existence, extinction and replacement of lineages occurring over the review period. Despite some gaps in the literature limiting the possibility for comparison, our review has described the molecular epidemiological trends of dengue infection. However, several gaps in molecular epidemiological information across Latin America and the Caribbean were identified that provide avenues for future research; in particular, sequence determination of the dengue virus genome is important for more precise phylogenetic classification and correlation with clinical outcome and disease severity.
Topics: Dengue; Dengue Virus; Humans; Latin America; Molecular Epidemiology; Phylogeny; South America
PubMed: 28068335
DOI: 10.1371/journal.pntd.0005224