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ACS Bio & Med Chem Au Jun 2024NS1 in flaviviruses is the only nonstructural protein that is secretory and interacts with different cellular components of the host cell membrane. NS1 is localized in...
Differences in the Membrane-Binding Properties of Flaviviral Nonstructural 1 (NS1) Protein: Comparative Simulations of Zika and Dengue Virus NS1 Proteins in Explicit Bilayers.
NS1 in flaviviruses is the only nonstructural protein that is secretory and interacts with different cellular components of the host cell membrane. NS1 is localized in the ER as a dimer to facilitate viral replication. Crystal structures of NS1 homologues from zika (ZIKV) and dengue (DENV) viruses have revealed the organization of different domains in NS1 dimers. The β-roll and the connector and intertwined loop regions of wing domains of NS1 have been shown to interact with the membranes. In this study, we have performed multiple molecular dynamics (MD) simulations of ZIKV and DENV NS1 systems in apo and in POPE bilayers with different cholesterol concentrations (0, 20 and 40%). The NS1 protein was placed just above the membrane surface, and for each NS1-membrane system two to three independent simulations with 600 ns production run were performed. At the end of the production runs, ZIKV NS1 inserts deeper inside the membrane compared to the DENV counterpart. Unlike ZIKV NS1, the orientation of DENV NS1 is asymmetric in which one of the chains in the dimer interacts with the membrane while the other is more exposed to the solvent. The β-roll region in ZIKV NS1 penetrates beyond the headgroup region and interacts with the lipid acyl chains while the C-terminal region barely interacts with the headgroup. Specific residues in the intertwined region deeply penetrate inside the membrane. The role of charged and aromatic residues of ZIKV NS1 in strongly interacting with the membrane components is revealed. The presence of cholesterol affects the extent of insertion in the membrane and interaction of individual residues. Overall, membrane-binding properties of ZIKV NS1 significantly differ from its counterpart in DENV. The differences found in the binding and insertion of NS1 can be used to design drugs and novel antibodies that can be flavivirus specific.
PubMed: 38911907
DOI: 10.1021/acsbiomedchemau.3c00073 -
Lancet Regional Health. Americas Jul 2024Dengue virus (DENV) is an arbovirus transmitted by mosquitoes, which can cause severe conditions such as hemorrhagic fever and dengue shock syndrome. These conditions...
BACKGROUND
Dengue virus (DENV) is an arbovirus transmitted by mosquitoes, which can cause severe conditions such as hemorrhagic fever and dengue shock syndrome. These conditions are associated with adverse social, clinical, and economic consequences in Brazil. Herein, the Wolbachia mosquito replacement method is a promising dengue control strategy.
METHODS
We estimated the economic impact of implementing the mosquito replacement method in seven Brazilian cities. A mathematical microsimulation model tracked nearly 23 million inhabitants over a 20-year period, considering the transitions between five different health states (susceptible, inapparent, outpatient, hospitalised and death). Direct costs included local dengue control programs, Wolbachia implementation and dengue care. Indirect costs related to death and productivity loss, as well as disability-adjusted life-years (DALY) averted were also considered.
FINDINGS
Without Wolbachia, the model projected 1,762,688 reported dengue cases over 20 years. Implementing the Wolbachia method would avert at least 1,295,566 dengue cases, resulting in lower costs and greater effectiveness in all simulated cities. On average, for every 1000 inhabitants followed for 20 years, the Wolbachia method yielded a cost difference of USD 538,233.68 (BRL 2,691,168.40) and averted 5.56 DALYs. Net monetary benefits (NMB) were positive in all seven cities, ranging from USD 110.72 (BRL 553.59) to USD 1399.19 (BRL 6995.95) per inhabitant. Alternative scenarios have also shown a favourable return on investment with a positive benefit-cost ratio (BCR).
INTERPRETATION
Wolbachia is likely a cost-effective strategy in the Brazilian context, consistent with international studies. Sensitivity analysis and alternative scenarios confirmed the robustness of the results.
FUNDING
This study was funded by the Wellcome Trust under a grant (224459/Z/21/Z).
PubMed: 38911346
DOI: 10.1016/j.lana.2024.100783 -
Antiviral Research Jun 2024Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites....
Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites. Dengue virus (DENV), a mosquito-borne flavivirus responsible for dengue fever, is no exception. Previous reports have documented DENV interactions with metabolic pathways and shown in particular that glycolysis is increased in DENV-infected cells. However, underlying molecular mechanisms are still poorly characterized and dependence of DENV on this pathway has not been investigated in details yet. Here, we identified an interaction between the non-structural protein 3 (NS3) of DENV and glucokinase regulator protein (GCKR), a host protein that inhibits the liver-specific hexokinase GCK. NS3 expression was found to increase glucose consumption and lactate secretion in hepatic cell line expressing GCK. Interestingly, we observed that GCKR interaction with GCK decreases DENV replication, indicating the dependence of DENV to GCK activity and supporting the role of NS3 as an inhibitor of GCKR function. Accordingly, in the same cells, DENV replication both induces and depends on glycolysis. By targeting NAD(H) biosynthesis with the antimetabolite 6-Amino-Nicotinamide (6-AN), we decreased cellular glycolytic activity and inhibited DENV replication in hepatic cells. Infection of primary organotypic liver cultures (OLiC) from hamsters was also inhibited by 6-AN. Altogether, our results show that DENV has evolved strategies to control glycolysis in the liver, which could account for hepatic dysfunctions associated to infection. Besides, our findings suggest that lowering intracellular availability of NAD(H) could be a valuable therapeutic strategy to control glycolysis and inhibit DENV replication in the liver.
PubMed: 38909960
DOI: 10.1016/j.antiviral.2024.105939 -
Infection, Genetics and Evolution :... Jun 2024Hainan Island and the Leizhou Peninsula, the southernmost part of mainland China, are areas where Aedes aegypti and Ae. albopictus are sympatric and are also...
BACKGROUND
Hainan Island and the Leizhou Peninsula, the southernmost part of mainland China, are areas where Aedes aegypti and Ae. albopictus are sympatric and are also high-incidence areas of dengue outbreaks in China. Many studies have suggested that Aedes endogenous viral components (EVEs) are enriched in piRNA clusters which can silence incoming viral genomes. Investigation the EVEs present in the piRNA clusters associated with viral infection of Aedes mosquitoes in these regions may provide a theoretical basis for novel transmission-blocking vector control strategies.
METHODS
In this study, specific primers for endogenous Flaviviridae elements (EFVEs) and endogenous Rhabdoviridae elements (ERVEs) were used to detect the distribution of Zika virus infection associated EVEs in the genomes of individuals of the two Aedes mosquitoes. Genetic diversity of EVEs with a high detection rate was also analyzed.
RESULTS
The results showed that many EVEs associated with Zika virus infection were detected in both Aedes species, with the detection rates were 47.68% to 100% in Ae. aegypti and 36.15% to 92.31% in sympatric Ae. albopictus populations. EVEs detection rates in another 17 Ae. albopictus populations ranged from 29.39% to 89.85%. Genetic diversity analyses of the four EVEs (AaFlavi53, AaRha61, AaRha91 and AaRha100) of Ae. aegypti showed that each had high haplotype diversity and low nucleotide diversity. The number of haplotypes in AaFlavi53 was 8, with the dominant haplotype being Hap_1 and the other 7 haplotypes being further mutated from Hap_1 in a lineage direction. In contrast, the haplotype diversity of the other three ERVEs (AaRha61, AaRha91 and AaRha100) was more diverse and richer, with the haplotype numbers were 9, 15 and 19 respectively. In addition, these EVEs all showed inconsistent patterns of both population differentiation and dispersal compared to neutral evolutionary genes such as the Mitochondrial COI gene.
CONCLUSION
The EFVEs and ERVEs tested were present at high frequencies in the field Aedes mosquito populations. The haplotype diversity of the EFVE AaFlavi53 was relatively lower and the three ERVEs (AaRha61, AaRha91, AaRha100) were higher. None of the four EVEs could be indicative of the genetic diversity of the Ae. aegypti population. This study provided theoretical support for the use of EVEs to block arbovirus transmission, but further research is needed into the mechanisms by which these EVEs are antiviral to Aedes mosquitoes.
PubMed: 38909667
DOI: 10.1016/j.meegid.2024.105627 -
Current Opinion in Insect Science Jun 2024Mosquito-borne diseases have a major impact on global human health. Biological agents that colonize the mosquito vector are increasingly explored as an intervention... (Review)
Review
Mosquito-borne diseases have a major impact on global human health. Biological agents that colonize the mosquito vector are increasingly explored as an intervention strategy to prevent vector-borne disease transmission. For instance, the release of mosquitoes carrying the endosymbiotic bacterium Wolbachia effectively reduced dengue virus incidence and disease. Insect-specific viruses are likewise considered as biocontrol agents against vector-borne diseases. While most studies focused on insect-specific viruses as an intervention against arthropod-borne viruses, we here consider whether mosquito-specific viruses may affect transmission of the malaria causing Plasmodium parasite by Anopheles mosquitoes. Although there is no direct experimental evidence addressing this question, we found that viral infections in dipteran insects activate some of the immune pathways that are antiparasitic in Anopheles. These findings suggest that indirect virus-parasite interactions could occur and that insect-specific viruses may modulate malaria transmission. Tripartite interactions between viruses, parasites, and Anopheles mosquitoes thus merit further investigation.
PubMed: 38908822
DOI: 10.1016/j.cois.2024.101222 -
PloS One 2024There have been several Viral Hemorrhagic Fever (VHF) outbreaks in Nigeria which remains a public health concern. Despite the increasing number of suspected cases of VHF...
There have been several Viral Hemorrhagic Fever (VHF) outbreaks in Nigeria which remains a public health concern. Despite the increasing number of suspected cases of VHF due to heightened surveillance activities and growing awareness, only a few cases are laboratory-confirmed to be VHF. Routinely, these samples are only tested for Lassa virus and Yellow fever virus with occasional testing for Dengue virus when indicated. The aetiology of the disease in these VHF suspected cases in Nigeria which are negative for Lassa, Yellow fever and Dengue viruses remains a puzzle. Since the clinical features exhibited by suspected VHF cases are like other endemic illnesses such as Hepatitis, there is a need to investigate the diversity and co-infections of hepatitis viruses as differentials and possible co-morbidity in suspected cases of VHFs in Nigeria. A total of three hundred and fifty (350) blood samples of 212 (60.6%) males and 138 (39.4%) females, aged <1-70 years with a mean age of 25 ±14.5, suspected of VHFs and tested negative for Lassa, Yellow fever and Dengue viruses were investigated for Hepatitis A, B, C and E viruses at the Centre for Human and Zoonotic Virology (CHAZVY), College of Medicine, University of Lagos (CMUL) using serologic and molecular techniques. The serologic analysis of these VHF suspected cases samples revealed that 126 (36%) were positive for at least one hepatitis virus. Individual prevalence for each of the hepatitis virus screened for showed that 37 (10.6%), 18 (5.1%) and 71 (20.3%) were positive for HBV, HCV and HEV respectively. All the samples were negative for HAV. A co-infection rate of 11.9% was also observed, with HCV/HEV co-infections being the most prevalent and the Northern region having the greatest burden of infection. The evidence of hepatitis virus infections in suspected cases of VHF was documented. Thus, their associations as co-morbidities and/or mortalities in this category of individuals require further investigations in endemic countries such as Nigeria. Therefore, the possible inclusion of screening for hepatitis viruses and other aetiologic agents that could mimic infections in suspected cases of VHFs in Nigeria should be thoroughly evaluated to guide informed policy on the diagnosis and management of these cases.
Topics: Humans; Nigeria; Male; Female; Adult; Adolescent; Middle Aged; Hemorrhagic Fevers, Viral; Child; Aged; Child, Preschool; Young Adult; Infant; Hepatitis Viruses; Coinfection
PubMed: 38905317
DOI: 10.1371/journal.pone.0305521 -
JAMA Jun 2024
PubMed: 38904971
DOI: 10.1001/jama.2024.10354 -
ELife Jun 2024Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the...
BACKGROUND
Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage.
METHODS
We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models.
RESULTS
Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5-6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes.
CONCLUSIONS
This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials.
FUNDING
Wellcome Trust and European Union Seventh Framework Programme.
Topics: Humans; Vietnam; Viremia; Platelet Count; Dengue; Male; Female; Adult; Kinetics; Middle Aged; Dengue Virus; Young Adult; Adolescent
PubMed: 38904662
DOI: 10.7554/eLife.92606 -
Cureus May 2024Introduction Dengue fever, caused by the dengue virus transmitted by Aedes aegypti mosquitoes, is a significant public health concern globally. Its resurgence in recent...
Introduction Dengue fever, caused by the dengue virus transmitted by Aedes aegypti mosquitoes, is a significant public health concern globally. Its resurgence in recent years, particularly in low- and middle-income countries, has led to increased morbidity and mortality rates. Atypical manifestations, involving the cardiac, liver, gut, renal, blood, bone, nervous, and respiratory systems, in dengue, can complicate both diagnosis and management. This study aimed to investigate the incidence of lung manifestations in dengue-infected individuals and their correlation with patient outcomes. Background The prevalence of dengue fever has risen dramatically over the past two decades, with Asia bearing the brunt of the burden, particularly India. The pathophysiology of lung complications in dengue remains unclear but is thought to be related to capillary leak syndrome and thrombocytopenia. Studies suggest that respiratory symptoms may be associated with severe cases and increased mortality rates. Despite limited research in India, understanding lung manifestations in dengue is crucial for improving diagnostic accuracy and patient care. Methods A retrospective study was conducted at K.S. Hegde Hospital, a tertiary care facility located in Mangalore, India, involving patients aged 18 years and above diagnosed with dengue fever between January and December 2019. Data gathered comprised patient demographics, clinical symptoms, laboratory findings, imaging results including radiographs, computed tomography (CT) scans of the chest (if accessible), ultrasound examinations of the chest and abdomen, and 2D echocardiograms, as well as patient outcomes. Diagnosis of lung manifestation was established through clinical assessment, chest X-ray interpretation, and ultrasound of the chest. Statistical analysis was conducted using SPSS Statistics (version 20), with a significance set at p<0.05. Results Out of 255 dengue cases, 10.19% (n=26) exhibited pulmonary manifestations, with pleural effusion being the most common. Older age (>50 years) and comorbidities were associated with a higher incidence of lung involvement. Respiratory symptoms, such as breathlessness, were more prevalent in patients with pulmonary complications. Laboratory parameters indicated distinct profiles in patients with lung manifestations, including elevated total count, urea, bilirubin, and liver enzymes, and reduced platelet counts. Mortality rates were higher in patients with lung involvement, older age, and comorbidities. Discussion The study findings highlight the importance of recognizing respiratory symptoms in dengue fever, particularly in older patients and those with underlying health conditions. The association between pulmonary involvement and adverse outcomes underscores the need for early detection and appropriate management strategies. Future research should focus on elucidating the pathophysiology of lung complications in dengue and developing targeted interventions to improve patient outcomes. Conclusion Lung manifestations in dengue fever represent a significant clinical challenge and are associated with increased morbidity and mortality. Early recognition of respiratory symptoms, along with prompt diagnostic evaluation and appropriate management, is essential for improving patient prognosis. Further studies are warranted to deepen our understanding of lung involvement in dengue and optimize therapeutic approaches to mitigate its impact on patient outcomes.
PubMed: 38903312
DOI: 10.7759/cureus.60655 -
Virology Journal Jun 2024Despite dengue virus (DENV) outbreak in Gabon a decade ago, less is known on the potential circulation of DENV serotypes in the country. Previous studies conducted in...
BACKGROUND
Despite dengue virus (DENV) outbreak in Gabon a decade ago, less is known on the potential circulation of DENV serotypes in the country. Previous studies conducted in some areas of the country, are limited to hospital-based surveys which reported the presence of some cases of serotype 2 and 3 seven years ago and more recently the serotype 1. As further investigation, we extend the survey to the community of Moyen Ogooué region with the aim to assess the presence of the dengue virus serotypes, additionally to characterize chikungunya (CHIKV) infection and describe the symptomatology associated with infections.
METHOD
A cross-sectional survey was conducted from April 2020 to March 2021. The study included participants of both sexes and any age one year and above, with fever or history of fever in the past seven days until blood collection. Eligible volunteers were clinically examined, and blood sample was collected for the detection of DENV and CHIKV using RT-qPCR. Positive samples were selected for the target sequencing.
RESULTS
A total of 579 volunteers were included. Their mean age (SD) was 20 (20) years with 55% of them being female. Four cases of DENV infection were diagnosed giving a prevalence of 0.7% (95%CI: 0.2-1.8) in our cohort while no case of CHIKV was detected. The common symptoms and signs presented by the DENV cases included fatigue, arthralgia myalgia, cough, and loss of appetite. DENV-1was the only virus detected by RT-qPCR.
CONCLUSION
Our results confirm the presence of active dengue infection in the region, particularly DENV-1, and could suggest the decline of DENV-2 and DENV-3. Continuous surveillance remains paramount to comprehensively describe the extent of dengue serotypes distribution in the Moyen-Ogooué region of Gabon.
Topics: Humans; Gabon; Dengue Virus; Female; Male; Dengue; Serogroup; Cross-Sectional Studies; Adult; Young Adult; Adolescent; Child, Preschool; Child; Middle Aged; Infant; Chikungunya Fever; Aged; Prevalence; Chikungunya virus
PubMed: 38902719
DOI: 10.1186/s12985-024-02406-x