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Viruses Feb 2024Dengue virus (DENV) is a prominent arbovirus with global spread, causing approximately 390 million infections each year. In Brazil, yearly epidemics follow a...
Dengue virus (DENV) is a prominent arbovirus with global spread, causing approximately 390 million infections each year. In Brazil, yearly epidemics follow a well-documented pattern of serotype replacement every three to four years on average. Araraquara, located in the state of São Paulo, has faced significant impacts from DENV epidemics since the emergence of DENV-1 in 2010. The municipality then transitioned from low to moderate endemicity in less than 10 years. Yet, there remains an insufficient understanding of virus circulation dynamics, particularly concerning DENV-1, in the region, as well as the genetic characteristics of the virus. To address this, we sequenced 37 complete or partial DENV-1 genomes sampled from 2015 to 2022 in Araraquara. Then, using also Brazilian and worldwide DENV-1 sequences we reconstructed the evolutionary history of DENV-1 in Araraquara and estimated the time to the most recent common ancestor (tMRCA) for serotype 1, for genotype V and its main lineages. Within the last ten years, there have been at least three introductions of genotype V in Araraquara, distributed in two main lineages (L Ia and L Ib, and L II). The tMRCA for the first sampled lineage (2015/2016 epidemics) was approximately 15 years ago (in 2008). Crucially, our analysis challenges existing assumptions regarding the emergence time of the DENV-1 genotypes, suggesting that genotype V might have diverged more recently than previously described. The presence of the two lineages of genotype V in the municipality might have contributed to the extended persistence of DENV-1 in the region.
Topics: Humans; Phylogeny; Dengue Virus; Dengue; Brazil; Genotype
PubMed: 38400049
DOI: 10.3390/v16020274 -
Trends in Molecular Medicine May 2024Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being... (Review)
Review
Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being overwhelmed. There are currently no specific treatments for dengue or prognostic markers to identify those who will progress to severe disease. Owing to an increase in the burden of illness and a change in epidemiology, many patients experience severe disease. Our limited understanding of the complex mechanisms of disease pathogenesis has significantly hampered the development of safe and effective treatments, vaccines, and biomarkers. We discuss the molecular mechanisms of dengue pathogenesis, the gaps in our knowledge, and recent advances, as well as the most crucial questions to be answered to enable the development of therapeutics, biomarkers, and vaccines.
Topics: Humans; Dengue; Dengue Virus; Animals; Biomarkers; Dengue Vaccines; Host-Pathogen Interactions
PubMed: 38582622
DOI: 10.1016/j.molmed.2024.03.006 -
Analytical Methods : Advancing Methods... Jun 2024Dengue virus (DENV) is the most prevalent global arbovirus, exhibiting a high worldwide incidence with intensified severity of symptoms and alarming mortality rates....
Dengue virus (DENV) is the most prevalent global arbovirus, exhibiting a high worldwide incidence with intensified severity of symptoms and alarming mortality rates. Faced with the limitations of diagnostic methods, an optical and electrochemical biosystem was developed for the detection of DENV genotypes 1 and 2, using cysteine (Cys), cadmium telluride (CdTe) quantum dots, and anti-DENV antibodies. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), surface plasmon resonance (SPR), atomic force microscopy (AFM), and Fourier transform infrared spectroscopy (FTIR) were employed to characterize the immunosensor. The AFM and SPR results demonstrated discernible topographic and angular changes confirming the biomolecular recognition. Different concentrations of DENV-1 and DENV-2 were evaluated (0.05 × 10 to 2.0 × 10 PFU mL), resulting in a maximum anodic shift (Δ%) of 263.67% ± 12.54 for DENV-1 and 63.36% ± 3.68 for DENV-2. The detection strategies exhibited a linear response to the increase in viral concentration. Excellent linear correlations, with values of 0.95391 for DENV-1 and 0.97773 for DENV-2, were obtained across a broad concentration range. Data analysis demonstrated high reproducibility, displaying relative standard deviation values of 3.42% and 3.62% for Cys-CdTe-antibody-BSA and Cys-CdTe-antibody-BSA systems. The detection limits were 0.34 × 10 PFU mL and 0.02 × 10 PFU mL, while the quantification limits were set at 1.49 × 10 PFU mL and 0.06 × 10 PFU mL for DENV-1 and DENV-2, respectively. Therefore, the biosensing apparatus demonstrates analytical effectiveness in viral screening and can be considered an innovative solution for early dengue diagnosis, contributing to global public health.
Topics: Dengue Virus; Biosensing Techniques; Tellurium; Humans; Dengue; Electrochemical Techniques; Quantum Dots; Surface Plasmon Resonance; Cysteine; Cadmium Compounds; Antibodies, Viral; Immunoassay; Limit of Detection; Microscopy, Atomic Force
PubMed: 38780022
DOI: 10.1039/d4ay00514g -
Journal of Medicinal Chemistry Jul 2023In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are...
In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates and with improved pan-serotype coverage (EC's against the four DENV serotypes ranging from 0.0011 to 0.24 μM for and from 0.00060 to 0.084 μM for ), chiral stability, and oral bioavailability in preclinical species, as well as showing a dose-proportional increase in efficacy against DENV-2 infection in vivo in mice.
Topics: Mice; Animals; Dengue Virus; Serogroup; Antiviral Agents; Dengue; Indoles
PubMed: 37389813
DOI: 10.1021/acs.jmedchem.3c00403 -
International Journal of Infectious... Aug 2023The origin and spread of dengue virus (DENV) circulating in Africa remain poorly characterized, with African sequences representing <1% of global sequence data.
OBJECTIVES
The origin and spread of dengue virus (DENV) circulating in Africa remain poorly characterized, with African sequences representing <1% of global sequence data.
METHODS
Whole genome sequencing was performed on serum samples (n = 29) from an undifferentiated fever study in 2016 in the Democratic Republic of Congo (DRC), and from febrile travelers returning from Africa. The evolutionary history of the newly acquired African DENV-1 (n = 1) and cosmopolitan genotype DENV-2 (n = 18) genomes was reconstructed using a phylogeographic, time-scaled Bayesian analysis on a curated DENV panel including all known African sequences.
RESULTS
A minimum of 10 and eight introductions could be identified into Africa for DENV-1 and cosmopolitan DENV-2, respectively, almost all originating from Asia. Three introductions were previously unknown. The currently circulating virus comprises mainly the recently introduced clades and one long-established African clade. Robust geographical clustering suggests limited spread of DENV after each introduction. Our data identified the DRC as the source of the 2018 Angolan DENV-2 epidemic, and similarly, the 2013 Angolan DENV-1 outbreak as the origin of our DRC study.
CONCLUSION
Active genomic surveillance of DENV in Africa at the portals of entry might help early outbreak response and limit sero- and genotype spread and human disease burden.
Topics: Humans; Dengue Virus; Dengue; Serogroup; Phylogeny; Bayes Theorem; Africa; Genotype; Disease Outbreaks; Fever
PubMed: 37088357
DOI: 10.1016/j.ijid.2023.04.391 -
PLoS Neglected Tropical Diseases Jan 2024Dengue is a mosquito-borne disease that has spread to over 100 countries. Its symptoms vary from the relatively mild acute febrile illness called dengue fever to the...
Dengue is a mosquito-borne disease that has spread to over 100 countries. Its symptoms vary from the relatively mild acute febrile illness called dengue fever to the much more severe dengue shock syndrome. Dengue is caused by dengue virus (DENV), which belongs to the Flavivirus genus of the family Flaviviridae. There are four serotypes of DENV, i.e., DENV1 to DENV4, and each serotype is divided into distinct genotypes. Thailand is an endemic area where all four serotypes of DENV co-circulate. Genome sequencing of the DENV2 that was isolated in Thailand in 2016 and 2017 revealed the emergence of the Cosmopolitan genotype and its co-circulation with the Asian-I genotype. However, it was unclear whether different genotypes have different levels of viral replication and pathogenicity. Focus-forming assay (FFA) results showed that clinical isolates of these genotypes differed in focus size and proliferative capacity. Using circular polymerase extension reaction, we generated parental and chimeric viruses with swapped genes between these two DENV2 genotypes, and compared their focus sizes and infectivity titers using FFA. The results showed that the focus size was larger when the structural proteins and/or non-structural NS1-NS2B proteins were derived from the Cosmopolitan virus. The infectious titers were consistent with the focus sizes. Single-round infectious particle assay results confirmed that chimeric viruses with Cosmopolitan type structural proteins, particularly prM/E, had significantly increased luciferase activity. Replicon assay results showed that Cosmopolitan NS1-NS2B proteins had increased reporter gene expression levels. Furthermore, in interferon-receptor knock-out mice, viruses with Cosmopolitan structural and NS1-NS2B proteins had higher titers in the blood, and caused critical disease courses. These results suggested that differences in the sequences within the structural and NS1-NS2B proteins may be responsible for the differences in replication, pathogenicity, and infectivity between the Asian-I and Cosmopolitan viruses.
Topics: Animals; Mice; Dengue Virus; Dengue; Virulence; Serogroup; Genotype; Virus Replication
PubMed: 38190404
DOI: 10.1371/journal.pntd.0011885 -
Science Translational Medicine Nov 2023Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has...
Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults ( = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop a susceptible-infected-recovered-susceptible (SIRS-type) model that tracks immunity by titer rather than number of infections to show that boosts in highly immune individuals can contribute to herd immunity, delaying their susceptibility to transmissible infection. In contrast, our model of lifelong immunity in highly immune individuals, as previously assumed, results in complete disease eradication after introduction. Periodic epidemics under this scenario can only be sustained with a constant influx of infected individuals into the population or a high basic reproductive number. We also find that Zika virus infection can boost DENV immunity and produce delays and then surges in dengue epidemics, as observed with real epidemiological data. This work provides insight into factors shaping periodicity in dengue incidence and may inform vaccine efforts to maintain population immunity.
Topics: Adult; Child; Humans; Dengue; Dengue Virus; Antibodies, Viral; Cross Reactions; Zika Virus Infection; Zika Virus
PubMed: 37967199
DOI: 10.1126/scitranslmed.adi1734 -
BioRxiv : the Preprint Server For... Sep 2023Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV...
Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.
PubMed: 37790301
DOI: 10.1101/2023.09.21.558875 -
Integrative and Comparative Biology Aug 2023Mosquitoes use a wide range of cues to find a host to feed on, eventually leading to the transmission of pathogens. Among them, olfactory cues (e.g., host-emitted odors,...
Mosquitoes use a wide range of cues to find a host to feed on, eventually leading to the transmission of pathogens. Among them, olfactory cues (e.g., host-emitted odors, including CO2, and skin volatiles) play a central role in mediating host-seeking behaviors. While mosquito olfaction can be impacted by many factors, such as the physiological state of the insect (e.g., age, reproductive state), the impact of environmental temperature on the olfactory system remains unknown. In this study, we quantified the behavioral responses of Aedes aegypti mosquitoes, vectors of dengue, yellow fever, and Zika viruses, among other pathogens, to host and plant-related odors under different environmental temperatures.
Topics: Animals; Dengue; Dengue Virus; Temperature; Smell; Mosquito Vectors; Zika Virus; Aedes; Zika Virus Infection
PubMed: 37309024
DOI: 10.1093/icb/icad066 -
EBioMedicine Aug 2023Dengue virus outbreaks are increasing in number and severity worldwide. Viral transmission is assumed to require a minimum time period of viral replication within the...
BACKGROUND
Dengue virus outbreaks are increasing in number and severity worldwide. Viral transmission is assumed to require a minimum time period of viral replication within the mosquito midgut. It is unknown if alternative transmission periods not requiring replication are possible.
METHODS
We used a mouse model of dengue virus transmission to investigate the potential of mechanical transmission of dengue virus. We investigated minimal viral titres necessary for development of symptoms in bitten mice and used resulting parameters to inform a new model of dengue virus transmission within a susceptible population.
FINDINGS
Naïve mice bitten by mosquitoes immediately after they took partial blood meals from dengue infected mice showed symptoms of dengue virus, followed by mortality. Incorporation of mechanical transmission into mathematical models of dengue virus transmission suggest that this supplemental transmission route could result in larger outbreaks which peak sooner.
INTERPRETATION
The potential of dengue transmission routes independent of midgut viral replication has implications for vector control strategies that target mosquito lifespan and suggest the possibility of similar mechanical transmission routes in other disease-carrying mosquitoes.
FUNDING
This study was funded by grants from the National Health Research Institutes, Taiwan (04D2-MMMOST02), the Human Frontier Science Program (RGP0033/2021), the National Institutes of Health (1R01AI143698-01A1, R01AI151004 and DP2AI152071) and the Ministry of Science and Technology, Taiwan (MOST104-2321-B-400-016).
Topics: Humans; Animals; Mice; Dengue Virus; Dengue; Aedes; Disease Outbreaks; Mosquito Vectors
PubMed: 37487418
DOI: 10.1016/j.ebiom.2023.104723