113 results on '"Ooi EE"'
Search Results
2. Is a therapeutic dengue monoclonal antibody on the way?
- Author
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Ooi EE and Chan YF
- Subjects
- Humans, Antibodies, Monoclonal therapeutic use, Dengue immunology, Dengue drug therapy, Antibodies, Viral therapeutic use, Dengue Virus immunology
- Abstract
Competing Interests: EEO collaborated with Visterra, which developed VIS513 during the pre-clinical stages of development but was not involved with the clinical trial. EEO has also served in advisory capacities to Takeda on dengue vaccine, and Janssen Pharmaceuticals and Novartis on dengue therapeutics. YFZC declared no competing interests.
- Published
- 2024
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3. Secreted dengue virus NS1 from infection is predominantly dimeric and in complex with high-density lipoprotein.
- Author
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Chew BLA, Ngoh ANQ, Phoo WW, Chan KWK, Ser Z, Tulsian NK, Lim SS, Weng MJG, Watanabe S, Choy MM, Low J, Ooi EE, Ruedl C, Sobota RM, Vasudevan SG, and Luo D
- Subjects
- Animals, Chlorocebus aethiops, Mice, Humans, Vero Cells, Apolipoprotein A-I metabolism, Apolipoprotein A-I chemistry, Protein Multimerization, Cryoelectron Microscopy, Viral Nonstructural Proteins metabolism, Viral Nonstructural Proteins chemistry, Viral Nonstructural Proteins genetics, Dengue Virus genetics, Dengue Virus metabolism, Lipoproteins, HDL metabolism, Dengue virology, Dengue metabolism
- Abstract
Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we obtained infection-derived sNS1 (isNS1) from dengue virus (DENV)-infected Vero cells through immunoaffinity purification instead of recombinant sNS1 (rsNS1) overexpressed in insect or mammalian cell lines. We found that isNS1 appeared as an approximately 250 kDa complex of NS1 and ApoA1 and further determined the cryoEM structures of isNS1 and its complex with a monoclonal antibody/Fab. Indeed, we found that the major species of isNS1 is a complex of the NS1 dimer partially embedded in a high-density lipoprotein (HDL) particle. Crosslinking mass spectrometry studies confirmed that the isNS1 interacts with the major HDL component ApoA1 through interactions that map to the NS1 wing and hydrophobic domains. Furthermore, our studies demonstrated that the sNS1 in sera from DENV-infected mice and a human patient form a similar complex as isNS1. Our results report the molecular architecture of a biological form of sNS1, which may have implications for the molecular pathogenesis of dengue., Competing Interests: BC, AN, WP, KC, ZS, NT, SL, MW, SW, MC, JL, EO, CR, RS, SV, DL No competing interests declared, (© 2023, Chew, Ngoh, Phoo et al.)
- Published
- 2024
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4. Proceedings of the 6th Asia Dengue Summit, June 2023.
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Srisawat N, Gubler DJ, Pangestu T, Limothai U, Thisyakorn U, Ismail Z, Goh D, Capeding MR, Bravo L, Yoksan S, Tantawichien T, Hadinegoro SR, Rafiq K, Picot VS, and Ooi EE
- Subjects
- Humans, Thailand, Public Health, World Health Organization, Asia, Southeastern epidemiology, Travel, Dengue epidemiology, Dengue prevention & control
- Abstract
The 6th Asia Dengue Summit (ADS) themed "Road Map to Zero Dengue Death" was held in Thailand from 15th-16th June 2023. The summit was hosted by Tropical Medicine Cluster, Chulalongkorn University, Bangkok, Thailand in conjunction with Queen Saovabha Memorial Institute, The Thai Red Cross Society; Faculty of Tropical Medicine, Mahidol University; and the Ministry of Public Health. The 6th ADS was convened by Asia Dengue Voice and Action (ADVA); Global Dengue and Aedes Transmitted Diseases Consortium (GDAC); Southeast Asian Ministers of Education Tropical Medicine and Public Health Network (SEAMEO TROPMED); Fondation Mérieux (FMx) and the International Society for Neglected Tropical Diseases (ISNTD). Dengue experts from academia and research, and representatives from the Ministries of Health, Regional and Global World Health Organization (WHO) and International Vaccine Institute (IVI) participated in the three-day summit. With more than 51 speakers and 451 delegates from over 24 countries, 10 symposiums, and 2 full days, the 6th ADS highlighted the growing threat of dengue and its antigenic evolution, flagged the urgent need to overcome vaccine hesitancy and misinformation crisis, and focused on dengue control policies, newer diagnostics, therapeutics and vaccines, travel-associated dengue, and strategies to improve community involvement., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Srisawat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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5. Race against dengue.
- Author
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Kwek SS and Ooi EE
- Subjects
- Humans, Viremia, Kinetics, Antibodies, Viral, Dengue epidemiology, Dengue Virus
- Abstract
Understanding the kinetics of dengue viruses in the bloodstream can provide insights into the clinical outcomes of the disease., Competing Interests: SK, EO No competing interests declared, (© 2024, Kwek and Ooi.)
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- 2024
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6. Dengue and Zika RNA-RNA interactomes reveal pro- and anti-viral RNA in human cells.
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Liao KC, Xie X, Sundstrom AKB, Lim XN, Tan KK, Zhang Y, Zou J, Bifani AM, Poh HX, Chen JJ, Ng WC, Lim SY, Ooi EE, Sessions OM, Tay Y, Shi PY, Huber RG, and Wan Y
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- Humans, RNA, Viral genetics, 3' Untranslated Regions, Virus Replication, Antiviral Agents, Dyneins genetics, Dyneins metabolism, Zika Virus genetics, Zika Virus Infection genetics, Dengue Virus genetics, Dengue Virus metabolism, Dengue genetics
- Abstract
Background: Identifying host factors is key to understanding RNA virus pathogenicity. Besides proteins, RNAs can interact with virus genomes to impact replication., Results: Here, we use proximity ligation sequencing to identify virus-host RNA interactions for four strains of Zika virus (ZIKV) and one strain of dengue virus (DENV-1) in human cells. We find hundreds of coding and non-coding RNAs that bind to DENV and ZIKV viruses. Host RNAs tend to bind to single-stranded regions along the virus genomes according to hybridization energetics. Compared to SARS-CoV-2 interactors, ZIKV-interacting host RNAs tend to be downregulated upon virus infection. Knockdown of several short non-coding RNAs, including miR19a-3p, and 7SK RNA results in a decrease in viral replication, suggesting that they act as virus-permissive factors. In addition, the 3'UTR of DYNLT1 mRNA acts as a virus-restrictive factor by binding to the conserved dumbbell region on DENV and ZIKV 3'UTR to decrease virus replication. We also identify a conserved set of host RNAs that interacts with DENV, ZIKV, and SARS-CoV-2, suggesting that these RNAs are broadly important for RNA virus infection., Conclusions: This study demonstrates that host RNAs can impact virus replication in permissive and restrictive ways, expanding our understanding of host factors and RNA-based gene regulation during viral pathogenesis., (© 2023. The Author(s).)
- Published
- 2023
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7. Insights into dengue immunity from vaccine trials.
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Ooi EE and Kalimuddin S
- Subjects
- Humans, Public Health, Immunity, Cellular, Dengue prevention & control
- Abstract
The quest for an effective dengue vaccine has culminated in two approved vaccines and another that has completed phase 3 clinical trials. However, shortcomings exist in each, suggesting that the knowledge on dengue immunity used to develop these vaccines was incomplete. Vaccine trial findings could refine our understanding of dengue immunity, because these are experimentally derived, placebo-controlled data. Results from these trials suggest that neutralizing antibody titers alone are insufficient to inform protection against symptomatic infection, implicating a role for cellular immunity in protection. These findings have relevance for both future dengue vaccine development and application of current vaccines for maximal public health benefit.
- Published
- 2023
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8. Externalities modulate the effectiveness of the Wolbachia release programme.
- Author
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Ooi EE and Wilder-Smith A
- Subjects
- Animals, Humans, Wolbachia, Aedes, Dengue
- Abstract
Competing Interests: We declare no competing interests. AW-S serves as a Consultant to WHO. The views and opinions expressed here are those of the author and not necessarily of WHO.
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- 2022
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9. Chronic sequelae complicate convalescence from both dengue and acute viral respiratory illness.
- Author
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Kalimuddin S, Teh YE, Wee LE, Paintal S, Sasisekharan R, Low JG, Sheth SK, and Ooi EE
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- Convalescence, Disease Progression, Humans, Male, Pandemics, Post-Acute COVID-19 Syndrome, COVID-19 complications, Dengue complications, Dengue epidemiology, Respiratory Tract Infections complications, Respiratory Tract Infections epidemiology
- Abstract
Long Covid has raised awareness of the potentially disabling chronic sequelae that afflicts patients after acute viral infection. Similar syndromes of post-infectious sequelae have also been observed after other viral infections such as dengue, but their true prevalence and functional impact remain poorly defined. We prospectively enrolled 209 patients with acute dengue (n = 48; one with severe dengue) and other acute viral respiratory infections (ARI) (n = 161), and followed them up for chronic sequelae up to one year post-enrolment, prior to the onset of the Covid-19 pandemic. Baseline demographics and co-morbidities were balanced between both groups except for gender, with more males in the dengue cohort (63% vs 29%, p<0.001). Except for the first visit, data on symptoms were collected remotely using a purpose-built mobile phone application. Mental health outcomes were evaluated using the validated SF-12v2 Health Survey. Almost all patients (95.8% of dengue and 94.4% of ARI patients) experienced at least one symptom of fatigue, somnolence, headache, concentration impairment or memory impairment within the first week of enrolment. Amongst patients with at least 3-months of follow-up, 18.0% in the dengue cohort and 14.6% in the ARI cohort experienced persistent symptoms. The median month-3 SF-12v2 Mental Component Summary Score was lower in patients who remained symptomatic at 3 months and beyond, compared to those whose symptoms fully resolved (47.7 vs. 56.0, p<0.001), indicating that patients who self-reported persistence of symptoms also experienced functionally worse mental health. No statistically significant difference in age, gender distribution or hospitalisation status was observed between those with and without chronic sequelae. Our findings reveal an under-appreciated burden of post-infection chronic sequelae in dengue and ARI patients. They call for studies to define the pathophysiology of this condition, and determine the efficacy of both vaccines as well as antiviral drugs in preventing such sequelae., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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10. TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection.
- Author
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Yousefi M, Lee WS, Yan B, Cui L, Yong CL, Yap X, Tay KSL, Qiao W, Tan D, Nurazmi NI, Linster M, Smith GJD, Lee YH, Carette JE, Ooi EE, Chan KR, and Ooi YS
- Subjects
- Energy Metabolism, Humans, Lipids, Membrane Proteins genetics, Virus Replication, Coronavirus, Coronavirus Infections, Dengue
- Abstract
Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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11. Metabolic Processes Are Differentially Regulated During Wild-Type and Attenuated Dengue Virus Infection in Aedes aegypti.
- Author
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Siriphanitchakorn T, Modahl CM, Kini RM, Ooi EE, and Choy MM
- Subjects
- Animals, Humans, Mosquito Vectors genetics, Transcriptome, Aedes genetics, Dengue, Dengue Virus genetics
- Abstract
Successful completion of the dengue virus (DENV) life cycle in its mosquito vectors is important for efficient human-mosquito-human cycle of transmission, but the virus-mosquito interactions that underpin this critical event are poorly defined. To understand the virus-host interactions that determine viral infection by Aedes aegypti, the principal DENV vector, the authors compared transcriptomic changes in the head/thorax of the mosquito after intrathoracic infection with the wild-type DENV2 16681 strain and its attenuated derivative, PDK53. Using high-throughput RNA-sequencing, the authors identified 1,629 differentially expressed genes (DEGs) during 16681 infection, compared with only 22 DEGs identified during PDK53 infection, indicating that 16681 infection triggers a more robust host transcriptomic response compared with PDK53 infection. The authors further found that 16681 infection, but not PDK53 infection, altered metabolism in these heads/thoraces. Altogether, our findings reveal differential regulation of metabolic processes during wild-type and attenuated DENV infection, and suggest the need for future work to study the role of metabolic processes in determining DENV infection and replication in its mosquito vectors.
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- 2022
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12. Implementation strategies for the first licensed dengue vaccine: A meeting report.
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Fongwen N, Delrieu I, Ham LH, Gubler DJ, Durbin A, Ooi EE, Peeling RW, Flasche S, Hartigan-Go K, Clifford S, Martinez CT, de Lamballerie X, Barnighausen T, and Wilder-Smith A
- Subjects
- Antibodies, Viral, Cost-Benefit Analysis, Humans, Vaccines, Attenuated, Dengue prevention & control, Dengue Vaccines, Dengue Virus
- Abstract
Dengue vaccination would enhance the control of dengue, one of the most frequent vector-borne viral diseases globally. CYD-TDV is the first dengue vaccine to be licensed, but global uptake has been hampered due to its use being limited to seropositive persons aged 9 years and above, and the need for a 3-dose schedule. The Partnership for Dengue Control (PDC) organized a meeting with key opinion leaders and stakeholders to deliberate on implementation strategies for the use of CYD-TDV. New data have emerged that support the shortening of the primary schedule from a 3 to 2 dose schedule, extending the age range below 9 to 6 years of age, and expanding the indication from endemic populations to also include travelers to endemic areas. Cost-effectiveness may improve with the modified 2-dose regimen and with multiple testing. Strategies to implement a dengue vaccination program have been developed, in particular school-based strategies. A range of delivery scenarios can then be considered, using various settings for each step of the intervention. However, several challenges remain, including communication about limiting the use of this vaccine to seropositive individuals only. Affordability will vary from country to country, as will government commitment and community acceptance. Well-tailored communication strategies that target key stakeholders are expected to make up a significant part of any future dengue vaccination program., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [RP is Director of the International Diagnostics Centre. AD is clinical trial principal investigator for the NIH dengue vaccine. EEO has served on various advisory boards for dengue vaccine developers including Sanofi Pasteur. AWS serves as consultant to WHO; statements presented here reflect her views and not necessarily those of WHO. KHG was a Department of Health Philippines official and one of many respondents to legal cases in the Philippines in relations to Dengvaxia vaccination causing deaths in children. ID works for the company EpiLinks, that receives funding from Fondation Mérieux and Sanofi Pasteur to develop a toolkit for dengue vaccine implementation. CTM has recerived honoraria for consultancies from Sanofi Pasteur.], (Copyright © 2021.)
- Published
- 2021
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13. Target product profile for a dengue pre-vaccination screening test.
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Fongwen N, Wilder-Smith A, Gubler DJ, Ooi EE, T Salvana EM, de Lamballerie X, Olliaro PL, and Peeling RW
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- Antibodies, Viral blood, Antibodies, Viral immunology, Dengue immunology, Humans, Mass Screening methods, Reference Standards, Sensitivity and Specificity, Vaccines, Attenuated, Dengue diagnosis, Dengue prevention & control, Dengue Vaccines immunology, Point-of-Care Testing, Serologic Tests methods, Vaccination
- Abstract
With increasing geographic spread, frequency, and magnitude of outbreaks, dengue continues to pose a major public health threat worldwide. Dengvaxia, a dengue live-attenuated tetravalent vaccine, was licensed in 2015, but post hoc analyses of long-term data showed serostatus-dependent vaccine performance with an excess risk of hospitalized and severe dengue in seronegative vaccine recipients. The World Health Organization (WHO) recommended that only persons with evidence of past dengue infection should receive the vaccine. A test for pre-vaccination screening for dengue serostatus is needed. To develop the target product profile (TPP) for a dengue pre-vaccination screening test, face-to-face consultative meetings were organized with follow-up regional consultations. A technical working group was formed to develop consensus on a reference test against which candidate pre-vaccination screening tests could be compared. The group also reviewed current diagnostic landscape and the need to accelerate the evaluation, regulatory approval, and policy development of tests that can identify seropositive individuals and maximize public health impact of vaccination while avoiding the risk of hospitalization in dengue-naive individuals. Pre-vaccination screening strategies will benefit from rapid diagnostic tests (RDTs) that are affordable, sensitive, and specific and can be used at the point of care (POC). The TPP described the minimum and ideal characteristics of a dengue pre-vaccination screening RDT with an emphasis on high specificity. The group also made suggestions for accelerating access to these RDTs through streamlining regulatory approval and policy development. Risk and benefit based on what can be achieved with RDTs meeting minimal and optimal characteristics in the TPP across a range of seroprevalences were defined. The final choice of RDTs in each country will depend on the performance of the RDT, dengue seroprevalence in the target population, tolerance of risk, and cost-effectiveness., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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14. Utilization of novel molecular multiplex methods for the detection and, epidemiological surveillance of dengue virus serotypes and chikungunya virus in Burkina Faso, West Africa.
- Author
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Gomgnimbou MK, Belem LRW, Some K, Diallo M, Barro B, Kaboré A, Hafalla JCR, and Sangaré I
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- Humans, Burkina Faso epidemiology, Middle Aged, Female, Adult, Adolescent, Aged, Male, Child, Preschool, Child, Serogroup, Aged, 80 and over, Multiplex Polymerase Chain Reaction methods, Young Adult, Epidemiological Monitoring, Animals, Aedes virology, Dengue Virus genetics, Dengue Virus isolation & purification, Chikungunya virus genetics, Chikungunya virus isolation & purification, Dengue epidemiology, Dengue virology, Dengue diagnosis, Dengue blood, Chikungunya Fever epidemiology, Chikungunya Fever virology, Chikungunya Fever diagnosis, Chikungunya Fever blood
- Abstract
Background: Dengue virus (DENV) and Chikungunya virus (CHIKV) are major arboviruses that are transmitted to humans by Aedes aegypti (A. aegypti) and Aedes Albopictus (A. Albopictus) mosquitoes. In absence of specific antivirals and vaccine against these two viruses, prompt diagnosis of acute infections and robust surveillance for outbreak identification remain crucial. Therefore, rapid, robust, high-throughput, accessible, and low-cost assays are essential for endemic countries. This study evaluated our recently developed multiplex RT-PCR and RT-qPCR assays to screen for DENV1-4 and CHIKV circulation in Burkina Faso., Methods and Results: This study, conducted between June to August 2023, enrolled patients with suspected arbovirus infection presenting at healthcare facilities in three Burkina Faso cities (Bobo-Dioulasso, Houndé, and Ouagadougou). Serum samples were collected and screened for DENV serotypes and CHIKV using our newly multiplex RT-PCR and RT-q PCR techniques recently developed. A total of 408 patients (age median = 33, range from 3 to 84 years) participated in this study. Of these, 13.7% (56/408) had DENV infection; DENV-1 was 32.1% (18/56) and DENV-3 was 67.9% (38/56). DENV-2, DENV-4 and CHIKV were not detected., Conclusions: This study demonstrates the effectiveness of our molecular methods for DENV detection and serotyping in Burkina Faso. The affordability of our methods makes them valuable for implementing widespread routine clinical diagnostics or arbovirus surveillance in resource-limited settings., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2024
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15. Antibody sugars are bittersweet.
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de Alwis R and Ooi EE
- Subjects
- Severity of Illness Index, Sugars, Dengue, Solanum
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- 2021
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16. Repurposing Ivermectin as an Anti-dengue Drug.
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Ooi EE
- Subjects
- Drug Repositioning, Humans, Ivermectin, Dengue drug therapy, Dengue Virus, Pharmaceutical Preparations
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- 2021
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17. Aviremic organ transplant dengue virus transmission - A case report.
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Sim JXY, Gan ES, Tan HC, Choy MM, Wong HM, Tan BH, Kee T, Ho QY, Thangaraju S, Lin RTP, Ooi EE, and Low JG
- Subjects
- Animals, Blood Donors, Humans, Viremia, Dengue diagnosis, Dengue Virus, Organ Transplantation
- Abstract
Dengue virus (DENV), a mosquito-borne pathogen, causes systemic infections. There are no clear guidelines regarding the screening of donor blood is used in endemic countries to prevent blood transfusion or transplant-associated dengue. DENV has been shown to be detected in urine samples even when DENV viremia is undetectable. We describe an incident of transplant-associated dengue where the donor tested negative for DENV viremia but positive for DENV viuria resulting in the transmission of DENV to our two kidney recipients. Both recipients resolved DENV infection uneventfully, with no adverse impact on the renal graft. Our findings raise the consideration for revised screening recommendations in endemic countries to include DENV RT-PCR in the urine., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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18. Challenges in prevaccination screening for previous dengue infection.
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Ooi EE
- Subjects
- Child, Enzyme-Linked Immunosorbent Assay, Humans, Immunoglobulin G, Neutralization Tests, Philippines, Prospective Studies, Dengue diagnosis, Dengue epidemiology, Dengue Virus
- Published
- 2021
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19. Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes.
- Author
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Gan ES, Tan HC, Le DHT, Huynh TT, Wills B, Seidah NG, Ooi EE, and Yacoub S
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- Adolescent, Adult, Cell Hypoxia, Cell Line, Child, Cholesterol metabolism, Dengue etiology, Drug Resistance, Viral, Female, Hepatocytes metabolism, Hepatocytes virology, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Male, Myeloid Cells metabolism, Myeloid Cells virology, Proprotein Convertase 9 blood, Receptors, LDL metabolism, Young Adult, Antiviral Agents pharmacology, Dengue drug therapy, Dengue metabolism, Dengue Virus pathogenicity, Proprotein Convertase 9 metabolism
- Abstract
Dengue virus (DENV) infection requires cholesterol as a proviral factor, although statin treatment did not show antiviral efficacy in patients with dengue. Here, we show that DENV infection manipulated cholesterol metabolism in cells residing in low-oxygen microenvironments (hypoxia) such as in the liver, spleen, and lymph nodes. DENV infection induced expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces low-density lipoprotein receptor (LDLR) recycling and hence cholesterol uptake. We found that, whereas LDLR uptake would have distributed cholesterol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the endoplasmic reticulum (ER). With cholesterol enrichment in the ER, ER-resident STING and type I IFN (IFN) activation was repressed during DENV infection. Our in vitro findings were further supported by the detection of elevated plasma PCSK9 levels in patients with dengue with high viremia and increased severity of plasma leakage. Our findings therefore suggest that PCSK9 plays a hitherto unrecognized role in dengue pathogenesis and that PCSK9 inhibitors could be a suitable host-directed treatment for patients with dengue.
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- 2020
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20. Preventing Dengue Epidemics during the COVID-19 Pandemic.
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Wilder-Smith A, Tissera H, Ooi EE, Coloma J, Scott TW, and Gubler DJ
- Subjects
- Animals, Betacoronavirus, COVID-19, Community Participation, Culicidae virology, Humans, Mosquito Control, Pandemics, Public Health, SARS-CoV-2, Tropical Climate, Coronavirus Infections epidemiology, Dengue prevention & control, Pneumonia, Viral epidemiology
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- 2020
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21. Positive epistasis between viral polymerase and the 3' untranslated region of its genome reveals the epidemiologic fitness of dengue virus.
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Syenina A, Vijaykrishna D, Gan ES, Tan HC, Choy MM, Siriphanitchakorn T, Cheng C, Vasudevan SG, and Ooi EE
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- A549 Cells, Dengue epidemiology, Epistasis, Genetic, Exoribonucleases, Gene Knockout Techniques, Genome, Viral, HEK293 Cells, Host-Pathogen Interactions, Humans, Interferon Type I metabolism, Microtubule-Associated Proteins, Mutation, Puerto Rico epidemiology, Virus Replication, 3' Untranslated Regions genetics, Dengue virology, Dengue Virus genetics, Viral Nonstructural Proteins genetics
- Abstract
Dengue virus (DENV) is a global health threat, causing repeated epidemics throughout the tropical world. While low herd immunity levels to any one of the four antigenic types of DENV predispose populations to outbreaks, viral genetic determinants that confer greater fitness for epidemic spread is an important but poorly understood contributor of dengue outbreaks. Here we report that positive epistasis between the coding and noncoding regions of the viral genome combined to elicit an epidemiologic fitness phenotype associated with the 1994 DENV2 outbreak in Puerto Rico. We found that five amino acid substitutions in the NS5 protein reduced viral genomic RNA (gRNA) replication rate to achieve a more favorable and relatively more abundant subgenomic flavivirus RNA (sfRNA), a byproduct of host 5'-3' exoribonuclease activity. The resulting increase in sfRNA relative to gRNA levels not only inhibited type I interferon (IFN) expression in infected cells through a previously described mechanism, but also enabled sfRNA to compete with gRNA for packaging into infectious particles. We suggest that delivery of sfRNA to new susceptible cells to inhibit type I IFN induction before gRNA replication and without the need for further de novo sfRNA synthesis could form a "preemptive strike" strategy against DENV., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
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22. Dengue pre-vaccination serology screening for the use of Dengvaxia®.
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Hunsperger E, Peeling R, Gubler DJ, and Ooi EE
- Subjects
- Antibodies, Viral blood, Dengue immunology, Dengue Virus immunology, Humans, Predictive Value of Tests, Seroepidemiologic Studies, Vaccination, Dengue diagnosis, Dengue prevention & control, Dengue Vaccines administration & dosage, Serologic Tests, Travel
- Published
- 2019
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23. Persistent Dengue Infection in an Immunosuppressed Patient Reveals the Roles of Humoral and Cellular Immune Responses in Virus Clearance.
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Ng KH, Zhang SL, Tan HC, Kwek SS, Sessions OM, Chan CY, Liu ID, Lee CK, Tambyah PA, Ooi EE, and Yap HK
- Subjects
- Aedes, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Cell Line, Cricetinae, Dengue complications, Female, Humans, Immunity, Cellular immunology, Immunity, Humoral immunology, Immunocompromised Host immunology, Kidney Transplantation, Lupus Erythematosus, Systemic complications, Lymphocyte Count, Lymphopenia complications, Lymphopenia immunology, RNA, Viral blood, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, CD8-Positive T-Lymphocytes immunology, Dengue immunology, Dengue Virus immunology
- Abstract
Detailed understanding of the roles of humoral and cellular immune responses in sterilizing dengue virus (DENV) infection in humans is required to inform effective vaccine development. We report an unusual case of persistent DENV infection in a lymphopenic renal transplant recipient who was therapeutically immunosuppressed to prevent organ rejection. Following resolution of symptomatic dengue, this patient remained positive for DENV3 RNA in the blood for 4 months and viruric up to 9 months post-infection despite demonstrable levels of serum neutralizing antibodies throughout this period. Full resolution of DENV infection instead coincided with recovery of CD8+ T cell counts during reversal from lymphopenia. Taken collectively, our observations suggest a role for cellular immunity in sterilizing DENV infection in humans. Any dengue vaccine should thus be able to induce both humoral and cellular immunity that respectively prevent symptomatic infection and enable effective viral clearance., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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24. Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review.
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Ghorai T, Sarkar A, Roy A, Bhowmick B, Nayak D, and Das S
- Subjects
- Humans, Dengue
- Abstract
A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis. Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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25. Detecting dengue fever in children using online Rasch analysis to develop algorithms for parents: An APP development and usability study.
- Author
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Hu TY, Chow JC, Chien TW, and Chou W
- Subjects
- Humans, Child, Bayes Theorem, Neural Networks, Computer, Parents, Algorithms, Dengue diagnosis
- Abstract
Background: Dengue fever (DF) is a significant public health concern in Asia. However, detecting the disease using traditional dichotomous criteria (i.e., absent vs present) can be extremely difficult. Convolutional neural networks (CNNs) and artificial neural networks (ANNs), due to their use of a large number of parameters for modeling, have shown the potential to improve prediction accuracy (ACC). To date, there has been no research conducted to understand item features and responses using online Rasch analysis. To verify the hypothesis that a combination of CNN, ANN, K-nearest-neighbor algorithm (KNN), and logistic regression (LR) can improve the ACC of DF prediction for children, further research is required., Methods: We extracted 19 feature variables related to DF symptoms from 177 pediatric patients, of whom 69 were diagnosed with DF. Using the RaschOnline technique for Rasch analysis, we examined 11 variables for their statistical significance in predicting the risk of DF. Based on 2 sets of data, 1 for training (80%) and the other for testing (20%), we calculated the prediction ACC by comparing the areas under the receiver operating characteristic curve (AUCs) between DF + and DF- in both sets. In the training set, we compared 2 scenarios: the combined scheme and individual algorithms., Results: Our findings indicate that visual displays of DF data are easily interpreted using Rasch analysis; the k-nearest neighbors algorithm has a lower AUC (<0.50); LR has a relatively higher AUC (0.70); all 3 algorithms have an almost equal AUC (=0.68), which is smaller than the individual algorithms of Naive Bayes, LR in raw data, and Naive Bayes in normalized data; and we developed an app to assist parents in detecting DF in children during the dengue season., Conclusion: The development of an LR-based APP for the detection of DF in children has been completed. To help patients, family members, and clinicians differentiate DF from other febrile illnesses at an early stage, an 11-item model is proposed for developing the APP., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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26. A T164S mutation in the dengue virus NS1 protein is associated with greater disease severity in mice.
- Author
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Chan KWK, Watanabe S, Jin JY, Pompon J, Teng D, Alonso S, Vijaykrishna D, Halstead SB, Marzinek JK, Bond PJ, Burla B, Torta F, Wenk MR, Ooi EE, and Vasudevan SG
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Conserved Sequence, Culicidae virology, Gene Expression Regulation, Inflammation genetics, Kinetics, Leukocytes, Mononuclear virology, Mice, Models, Molecular, Mutant Proteins chemistry, Phylogeny, Protein Multimerization, Protein Stability, Viral Nonstructural Proteins chemistry, Virus Replication, Dengue pathology, Dengue virology, Dengue Virus genetics, Mutation genetics, Severity of Illness Index, Viral Nonstructural Proteins genetics
- Abstract
Dengue viruses cause severe and sudden human epidemics worldwide. The secreted form of the nonstructural protein 1 (sNS1) of dengue virus causes vascular leakage, a hallmark of severe dengue disease. Here, we reverse engineered the T164S mutation of NS1, associated with the severity of dengue epidemics in the Americas, into a dengue virus serotype 2 mildly infectious strain. The T164S mutant virus decreased infectious virus production and increased sNS1 production in mammalian cell lines and human peripheral blood mononuclear cells (PBMCs) without affecting viral RNA replication. Gene expression profiling of 268 inflammation-associated human genes revealed up-regulation of genes induced in response to vascular leakage. Infection of the mosquito vector Aedes aegypti with the T164S mutant virus resulted in increased viral load in the mosquito midgut and higher sNS1 production compared to wild-type virus infection. Infection of type 1 and 2 interferon receptor-deficient AG129 mice with the T164S mutant virus resulted in severe disease coupled with increased complement activation, tissue inflammation, and more rapid mortality compared to AG129 mice infected with wild-type virus. Molecular dynamics simulations predicted that mutant sNS1 formed stable dimers similar to the wild-type protein, whereas the hexameric mutant sNS1 was predicted to be unstable. Immunoaffinity-purified sNS1 from T164S mutant virus-infected mammalian cells was associated with different lipid classes compared to wild-type sNS1. Treatment of human PBMCs with sNS1 purified from T164S mutant virus resulted in a twofold higher production of proinflammatory cytokines, suggesting a mechanism for how mutant sNS1 may cause more severe dengue disease., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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27. Dengue Mosaic Vaccines Enhance Cellular Immunity and Expand the Breadth of Neutralizing Antibody Against All Four Serotypes of Dengue Viruses in Mice.
- Author
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Hou J, Shrivastava S, Fraser CC, Loo HL, Wong LH, Ho V, Fink K, Ooi EE, and Chen J
- Subjects
- Animals, Female, Mice, Serogroup, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Dengue genetics, Dengue immunology, Dengue prevention & control, Dengue Vaccines genetics, Dengue Vaccines immunology, Dengue Virus genetics, Dengue Virus immunology, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology
- Abstract
An estimated 400 million people in the world are infected with any of the four types of dengue virus (DENV) annually. The only licensed dengue vaccine cannot effectively prevent infection with all of the four DENVs, especially in those immunologically naïve at baseline. In this study, we explored a mosaic vaccine approach, which utilizes an artificial recombinant sequence for each serotype to achieve maximum coverage of variant epitopes in the four DENVs. We determined the immunogenicity and cross-reactivity of DNA plasmids encoding individual mosaic sequences or the natural sequences in mice. We show that the mosaic vaccines, particularly those targeting DENV serotype 1 and 2, improved vaccine immunogenicity by increasing the percentage of antigen-specific IFNγ- or TNFα-secreting CD4 and CD8 T cells, and titers of neutralizing antibodies. The mosaic vaccine diversified and broadened anti-dengue T cell responses and cross-reactive neutralizing antibodies against all four serotypes. The mosaic vaccines also induced higher level of antigen-specific B cell responses. These results suggest that mosaic vaccines comprising of DENV serotype 1 and 2 variant epitopes could stimulate strong and broad immune responses against all four serotypes.
- Published
- 2019
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28. Dengue.
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Wilder-Smith A, Ooi EE, Horstick O, and Wills B
- Subjects
- Animals, Arthropod Vectors, Drug Discovery, Global Health, Humans, Serogroup, Vaccination methods, Dengue epidemiology, Dengue Vaccines, Dengue Virus pathogenicity, Nucleic Acid Amplification Techniques methods
- Abstract
Mortality from severe dengue is low, but the economic and resource burden on health services remains substantial in endemic settings. Unfortunately, progress towards development of effective therapeutics has been slow, despite notable advances in the understanding of disease pathogenesis and considerable investment in antiviral drug discovery. For decades antibody-dependent enhancement has been the prevalent model to explain dengue pathogenesis, but it was only recently demonstrated in vivo and in clinical studies. At present, the current mainstay of management for most symptomatic dengue patients remains careful observation and prompt but judicious use of intravenous hydration therapy for those with substantial vascular leakage. Various new promising technologies for diagnosis of dengue are currently in the pipeline. New sample-in, answer-out nucleic acid amplification technologies for point-of-care use are being developed to improve performance over current technologies, with the potential to test for multiple pathogens using a single specimen. The search for biomarkers that reliably predict development of severe dengue among symptomatic individuals is also a major focus of current research efforts. The first dengue vaccine was licensed in 2015 but its performance depends on serostatus. There is an urgent need to identify correlates of both vaccine protection and disease enhancement. A crucial assessment of vector control tools should guide a research agenda for determining the most effective interventions, and how to best combine state-of-the-art vector control with vaccination., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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29. Identification and characterization of host proteins bound to dengue virus 3' UTR reveal an antiviral role for quaking proteins.
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Liao KC, Chuo V, Ng WC, Neo SP, Pompon J, Gunaratne J, Ooi EE, and Garcia-Blanco MA
- Subjects
- Dengue genetics, Dengue virology, Genome, Viral, HEK293 Cells, Humans, RNA-Binding Proteins genetics, 3' Untranslated Regions, Antiviral Agents pharmacology, Dengue prevention & control, Dengue Virus drug effects, RNA, Viral genetics, RNA-Binding Proteins metabolism, Virus Replication drug effects
- Abstract
The four dengue viruses (DENV1-4) are rapidly reemerging infectious RNA viruses. These positive-strand viral genomes contain structured 3' untranslated regions (UTRs) that interact with various host RNA binding proteins (RBPs). These RBPs are functionally important in viral replication, pathogenesis, and defense against host immune mechanisms. Here, we combined RNA chromatography and quantitative mass spectrometry to identify proteins interacting with DENV1-4 3' UTRs. As expected, RBPs displayed distinct binding specificity. Among them, we focused on quaking (QKI) because of its preference for the DENV4 3' UTR (DENV-4/SG/06K2270DK1/2005). RNA immunoprecipitation experiments demonstrated that QKI interacted with DENV4 genomes in infected cells. Moreover, QKI depletion enhanced infectious particle production of DENV4. On the contrary, QKI did not interact with DENV2 3' UTR, and DENV2 replication was not affected consistently by QKI depletion. Next, we mapped the QKI interaction site and identified a QKI response element (QRE) in DENV4 3' UTR. Interestingly, removal of QRE from DENV4 3' UTR abolished this interaction and increased DENV4 viral particle production. Introduction of the QRE to DENV2 3' UTR led to QKI binding and reduced DENV2 infectious particle production. Finally, reporter assays suggest that QKI reduced translation efficiency of viral RNA. Our work describes a novel function of QKI in restricting viral replication., (© 2018 Liao et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)
- Published
- 2018
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30. Neutralization of antibody-enhanced dengue infection by VIS513, a pan serotype reactive monoclonal antibody targeting domain III of the dengue E protein.
- Author
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Budigi Y, Ong EZ, Robinson LN, Ong LC, Rowley KJ, Winnett A, Tan HC, Hobbie S, Shriver Z, Babcock GJ, Alonso S, and Ooi EE
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Viral administration & dosage, Antibodies, Viral blood, Antibodies, Viral genetics, Antigens, Viral chemistry, Antigens, Viral genetics, Cell Line, Chlorocebus aethiops, Cross Reactions immunology, Dengue Virus genetics, Dengue Virus pathogenicity, Disease Models, Animal, Epitopes, Female, Humans, Immune Sera, Immunotherapy, In Vitro Techniques, Mice, Models, Structural, Mutation, Neutralization Tests, Protein Conformation, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins immunology, Serogroup, THP-1 Cells, Vero Cells, Viral Envelope Proteins chemistry, Viral Envelope Proteins genetics, Viral Plaque Assay, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Dengue immunology, Dengue Virus immunology, Viral Envelope Proteins immunology
- Abstract
Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible.
- Published
- 2018
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31. Dengue vaccine-induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies.
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Lam JH, Chua YL, Lee PX, Martínez Gómez JM, Ooi EE, and Alonso S
- Subjects
- Animals, Antibodies, Neutralizing immunology, Antibodies, Viral biosynthesis, Antibodies, Viral immunology, Dengue immunology, Dengue Virus immunology, Female, Immunity, Cellular, Immunity, Maternally-Acquired, Male, Maternal-Fetal Exchange immunology, Mice, 129 Strain, Pregnancy, Seroconversion, CD8-Positive T-Lymphocytes immunology, Dengue prevention & control, Dengue Vaccines immunology
- Abstract
Declining levels of maternal antibodies were shown to sensitize infants born to dengue-immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur's chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises 2 questions: will declining levels of maternal vaccine-induced antibodies cause ADE; and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modeled in mice. Type I IFN-deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of the tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P-PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination, owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies.
- Published
- 2017
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32. Temporary Cross-Immunity as a Plausible Driver of Asynchronous Cycles of Dengue Serotypes.
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Fung T, Clapham HE, and Chisholm RA
- Subjects
- Humans, Serogroup, Mathematical Concepts, Models, Biological, Coinfection, Dengue epidemiology
- Abstract
Many infectious diseases exist as multiple variants, with interactions between variants potentially driving epidemiological dynamics. These diseases include dengue, which infects hundreds of millions of people every year and exhibits complex multi-serotype dynamics. Antibodies produced in response to primary infection by one of the four dengue serotypes can produce a period of temporary cross-immunity (TCI) to infection by other serotypes. After this period, the remaining antibodies can facilitate the entry of heterologous serotypes into target cells, thus enhancing severity of secondary infection by a heterologous serotype. This represents antibody-dependent enhancement (ADE). In this study, we analyze an epidemiological model to provide novel insights into the importance of TCI and ADE in producing cyclic outbreaks of dengue serotypes. Our analyses reveal that without TCI, such cyclic outbreaks are synchronous across serotypes and only occur when ADE produces high transmission rates. In contrast, the presence of TCI allows asynchronous cycles of serotypes by inducing a time lag between recovery from primary infection by one serotype and secondary infection by another, with such cycles able to occur without ADE. Our results suggest that TCI is a fundamental driver of asynchronous cycles of dengue serotypes and possibly other multi-variant diseases., (© 2023. The Author(s), under exclusive licence to Society for Mathematical Biology.)
- Published
- 2023
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33. Facilitators and barriers to engaging communities in health service research on dengue control in Indo-Pacific region: a systematic review.
- Author
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Naing C, Htet NH, Tung WS, Aung HH, and Whittaker MA
- Subjects
- Child, Humans, Community Participation, Qualitative Research, Vietnam, Dengue epidemiology, Dengue prevention & control, Public Health
- Abstract
Background: Dengue is a public health problem in the Indo-Pacific countries. There are concerns over the facilitators and barriers to community engagement in health service research aimed at dengue control. The objective of his study was to identify and synthesize facilitators and barriers to community engagement in health service research aimed at dengue control., Methodology: The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist was used to perform this review. Health-related databases including PubMed, Ovid, and Google Scholar were searched for relevant studies. A consolidated framework with five domains was developed after undertaking a six-phase reflective thematic assessment of the data., Results: Thirteen studies were identified, spanning eight low-and middle-income countries of the Indo-Pacific region including Cambodia, India, Indonesia, Myanmar, Philippines, Sri Lanka, Thailand, and Vietnam. The studies in this review covered the period from 2002 to 2021. A broad range of study designs and objectives were revealed across these 13 studies. An array of communities such as the local government, project-related health staff, local health services staff, community leaders, local communities/residences/general public, heads of households, community health volunteers, school teachers, and schoolchildren participated in these dengue related studies. The five Consolidated Framework for Implementation Research (CFIR) domains of 'intervention characteristics', 'inner setting', 'outer setting',' individual characteristics', and 'program implementations' were used to identify and describe barriers and facilitators., Conclusions: The findings indicate a range of barriers and facilitators to community engagement in dengue control in the selected LMIC in the Indo-Pacific countries. Future health services research on dengue control approaches should be carefully planned, methodologically constructed, aligned with community engagement principles, and involve considerable community participation at all stages of the research., (© 2023. BioMed Central Ltd., part of Springer Nature.)
- Published
- 2023
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34. Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules.
- Author
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Costa VV, Ye W, Chen Q, Teixeira MM, Preiser P, Ooi EE, and Chen J
- Subjects
- Animals, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte genetics, Cell Adhesion Molecules antagonists & inhibitors, Dendritic Cells immunology, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukin-2 Receptor alpha Subunit genetics, Lectins, C-Type genetics, Liver pathology, Lymphocyte Activation, Mice, Mice, SCID, Monocytes immunology, Thrombocytopenia virology, Viremia, Virus Replication, Cell Adhesion Molecules metabolism, Dendritic Cells virology, Dengue immunology, Dengue Virus immunology, Killer Cells, Natural immunology, Monocytes virology
- Abstract
Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo , identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection., (Copyright © 2017 Costa et al.)
- Published
- 2017
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35. Preclinical evaluation of VIS513, a therapeutic antibody against dengue virus, in non-human primates.
- Author
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Ong EZ, Budigi Y, Tan HC, Robinson LN, Rowley KJ, Winnett A, Hobbie S, Shriver Z, Babcock GJ, and Ooi EE
- Subjects
- Animals, Drug Evaluation, Preclinical, Macaca, Treatment Outcome, Antibodies, Viral administration & dosage, Antiviral Agents administration & dosage, Dengue therapy, Dengue Virus immunology, Immunologic Factors administration & dosage, Immunotherapy methods
- Abstract
Despite useful in vivo activity, no therapeutic against dengue virus (DENV) has demonstrated efficacy in clinical trials. Herein, we explored dosing and virological endpoints to guide the design of human trials of VIS513, a pan-serotype anti-DENV IgG1 antibody, in non-human primates (NHPs). Dosing VIS513 pre- or post-peak viremia in NHPs neutralized infectious DENV although RNAemia remained detectable post-treatment; differential interaction of human IgGs with macaque Fc-gamma receptors may delay clearance of neutralized DENV. Our findings suggest useful antiviral utility of VIS513 and highlight an important consideration when evaluating virological endpoints of trials for anti-DENV biologics., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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36. Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission.
- Author
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Pompon J, Manuel M, Ng GK, Wong B, Shan C, Manokaran G, Soto-Acosta R, Bradrick SS, Ooi EE, Missé D, Shi PY, and Garcia-Blanco MA
- Subjects
- Animals, Dengue virology, Dengue Virus genetics, Humans, RNA, Viral genetics, RNA, Viral metabolism, Salivary Glands immunology, Salivary Glands virology, Virus Replication, Aedes immunology, Aedes virology, Dengue transmission, Dengue Virus physiology, Insect Vectors immunology, Insect Vectors virology
- Abstract
Globally re-emerging dengue viruses are transmitted from human-to-human by Aedes mosquitoes. While viral determinants of human pathogenicity have been defined, there is a lack of knowledge of how dengue viruses influence mosquito transmission. Identification of viral determinants of transmission can help identify isolates with high epidemiological potential. Additionally, mechanistic understanding of transmission will lead to better understanding of how dengue viruses harness evolution to cycle between the two hosts. Here, we identified viral determinants of transmission and characterized mechanisms that enhance production of infectious saliva by inhibiting immunity specifically in salivary glands. Combining oral infection of Aedes aegypti mosquitoes and reverse genetics, we identified two 3' UTR substitutions in epidemic isolates that increased subgenomic flaviviral RNA (sfRNA) quantity, infectious particles in salivary glands and infection rate of saliva, which represents a measure of transmission. We also demonstrated that various 3'UTR modifications similarly affect sfRNA quantity in both whole mosquitoes and human cells, suggesting a shared determinism of sfRNA quantity. Furthermore, higher relative quantity of sfRNA in salivary glands compared to midgut and carcass pointed to sfRNA function in salivary glands. We showed that the Toll innate immune response was preferentially inhibited in salivary glands by viruses with the 3'UTR substitutions associated to high epidemiological fitness and high sfRNA quantity, pointing to a mechanism for higher saliva infection rate. By determining that sfRNA is an immune suppressor in a tissue relevant to mosquito transmission, we propose that 3'UTR/sfRNA sequence evolution shapes dengue epidemiology not only by influencing human pathogenicity but also by increasing mosquito transmission, thereby revealing a viral determinant of epidemiological fitness that is shared between the two hosts.
- Published
- 2017
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37. Serial Metabolome Changes in a Prospective Cohort of Subjects with Influenza Viral Infection and Comparison with Dengue Fever.
- Author
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Cui L, Fang J, Ooi EE, and Lee YH
- Subjects
- Adult, Dengue diagnosis, Dengue virology, Dengue Virus pathogenicity, Dengue Virus physiology, Fatty Acids blood, Female, Gonadal Steroid Hormones blood, Gonadal Steroid Hormones genetics, Host-Pathogen Interactions, Humans, Influenza A Virus, H3N2 Subtype pathogenicity, Influenza A Virus, H3N2 Subtype physiology, Influenza, Human diagnosis, Influenza, Human virology, Lipoxygenase blood, Lipoxygenase genetics, Male, Middle Aged, Oxidation-Reduction, Phospholipids blood, Prospective Studies, Purines blood, Tryptophan blood, Dengue blood, Influenza, Human blood, Lipid Metabolism genetics, Metabolic Networks and Pathways genetics, Metabolome
- Abstract
Influenza virus infection (IVI) and dengue virus infection (DVI) are major public health threats. Between IVI and DVI, clinical symptoms can be overlapping yet infection-specific, but host metabolome changes are not well-described. Untargeted metabolomics and targeted oxylipinomic analyses were performed on sera serially collected at three phases of infection from a prospective cohort study of adult subjects with either H3N2 influenza infection or dengue fever. Untargeted metabolomics identified 26 differential metabolites, and major perturbed pathways included purine metabolism, fatty acid biosynthesis and β-oxidation, tryptophan metabolism, phospholipid catabolism, and steroid hormone pathway. Alterations in eight oxylipins were associated with the early symptomatic phase of H3N2 flu infection, were mostly arachidonic acid-derived, and were enriched in the lipoxygenase pathway. There was significant overlap in metabolome profiles in both infections. However, differences specific to IVI and DVI were observed. DVI specifically attenuated metabolites including serotonin, bile acids and biliverdin. Additionally, metabolome changes were more persistent in IVI in which metabolites such as hypoxanthine, inosine, and xanthine of the purine metabolism pathway remained significantly elevated at 21-27 days after fever onset. This study revealed the dynamic metabolome changes in IVI subjects and provided biochemical insights on host physiological similarities and differences between IVI and DVI.
- Published
- 2017
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38. Serum Metabolomics Investigation of Humanized Mouse Model of Dengue Virus Infection.
- Author
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Cui L, Hou J, Fang J, Lee YH, Costa VV, Wong LH, Chen Q, Ooi EE, Tannenbaum SR, Chen J, and Ong CN
- Subjects
- Animals, Disease Models, Animal, Mass Spectrometry, Metabolomics, Mice, Mice, SCID, Time Factors, Dengue pathology, Metabolome, Serum chemistry
- Abstract
Dengue is an acute febrile illness caused by dengue virus (DENV) and a major cause of morbidity and mortality in tropical and subtropical regions of the world. The lack of an appropriate small-animal model of dengue infection has greatly hindered the study of dengue pathogenesis and the development of therapeutics. In this study, we conducted mass spectrometry-based serum metabolic profiling from a model using humanized mice (humice) with DENV serotype 2 infection at 0, 3, 7, 14, and 28 days postinfection (dpi). Forty-eight differential metabolites were identified, including fatty acids, purines and pyrimidines, acylcarnitines, acylglycines, phospholipids, sphingolipids, amino acids and derivatives, free fatty acids, and bile acid. These metabolites showed a reversible-change trend-most were significantly perturbed at 3 or 7 dpi and returned to control levels at 14 or 28 dpi, indicating that the metabolites might serve as prognostic markers of the disease in humice. The major perturbed metabolic pathways included purine and pyrimidine metabolism, fatty acid β-oxidation, phospholipid catabolism, arachidonic acid and linoleic acid metabolism, sphingolipid metabolism, tryptophan metabolism, phenylalanine metabolism, lysine biosynthesis and degradation, and bile acid biosynthesis. Most of these disturbed pathways are similar to our previous metabolomics findings in a longitudinal cohort of adult human dengue patients across different infection stages. Our analyses revealed the commonalities of host responses to DENV infection between humice and humans and suggested that humice could be a useful small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics. IMPORTANCE Dengue virus is the most widespread arbovirus, causing an estimated 390 million dengue infections worldwide every year. There is currently no effective treatment for the disease, and the lack of an appropriate small-animal model of dengue infection has greatly increased the challenges in the study of dengue pathogenesis and the development of therapeutics. Metabolomics provides global views of small-molecule metabolites and is a useful tool for finding metabolic pathways related to disease processes. Here, we conducted a serum metabolomics study on a model using humanized mice with dengue infection that had significant levels of human platelets, monocytes/macrophages, and hepatocytes. Forty-eight differential metabolites were identified, and the underlying perturbed metabolic pathways are quite similar to the pathways found to be altered in dengue patients in previous metabolomics studies, indicating that humanized mice could be a highly relevant small-animal model for the study of dengue pathogenesis and the development of dengue therapeutics., (Copyright © 2017 Cui et al.)
- Published
- 2017
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39. Hypoxia enhances antibody-dependent dengue virus infection.
- Author
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Gan ES, Cheong WF, Chan KR, Ong EZ, Chai X, Tan HC, Ghosh S, Wenk MR, and Ooi EE
- Subjects
- Cell Membrane metabolism, Cells, Cultured, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lipid Metabolism, Receptors, IgG metabolism, Antibodies, Viral metabolism, Antibody-Dependent Enhancement, Dengue pathology, Dengue Virus growth & development, Hypoxia, Monocytes virology
- Abstract
Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post-mortem analysis. These organs are known to have low oxygen levels (~0.5-4.5% O
2 ) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia-induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2 show greater susceptibility to antibody-dependent enhancement of DENV infection. Low oxygen level induces HIF1α-dependent upregulation of fragment crystallizable gamma receptor IIA (FcγRIIA) as well as HIF1α-independent alterations in membrane ether lipid concentrations. The increased FcγRIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody-dependent but hypoxia-induced and suggest a role for targeting hypoxia-induced factors for anti-dengue therapy., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2017
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40. Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial.
- Author
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Lye DC, Archuleta S, Syed-Omar SF, Low JG, Oh HM, Wei Y, Fisher D, Ponnampalavanar SSL, Wijaya L, Lee LK, Ooi EE, Kamarulzaman A, Lum LC, Tambyah PA, and Leo YS
- Subjects
- Adult, Equivalence Trials as Topic, Female, Hemorrhage etiology, Humans, Malaysia, Male, Middle Aged, Singapore, Treatment Outcome, Dengue complications, Hemorrhage prevention & control, Platelet Transfusion, Thrombocytopenia complications
- Abstract
Background: Dengue is the commonest vector-borne infection worldwide. It is often associated with thrombocytopenia, and prophylactic platelet transfusion is widely used despite the dearth of robust evidence. We aimed to assess the efficacy and safety of prophylactic platelet transfusion in the prevention of bleeding in adults with dengue and thrombocytopenia., Methods: We did an open-label, randomised, superiority trial in five hospitals in Singapore and Malaysia. We recruited patients aged at least 21 years who had laboratory-confirmed dengue (confirmed or probable) and thrombocytopenia (≤20 000 platelets per μL), without persistent mild bleeding or any severe bleeding. Patients were assigned (1:1), with randomly permuted block sizes of four or six and stratified by centre, to receive prophylactic platelet transfusion in addition to supportive care (transfusion group) or supportive care alone (control group). In the transfusion group, 4 units of pooled platelets were given each day when platelet count was 20 000 per μL or lower; supportive care consisted of bed rest, fluid therapy, and fever and pain medications. The primary endpoint was clinical bleeding (excluding petechiae) by study day 7 or hospital discharge (whichever was earlier), analysed by intention to treat. Safety outcomes were analysed according to the actual treatment received. This study was registered with ClinicalTrials.gov, number NCT01030211, and is completed., Findings: Between April 29, 2010, and Dec 9, 2014, we randomly assigned 372 patients to the transfusion group (n=188) or the control group (n=184). The intention-to-treat analysis included 187 patients in the transfusion group (one patient was withdrawn immediately) and 182 in the control group (one was withdrawn immediately and one did not have confirmed or probable dengue). Clinical bleeding by day 7 or hospital discharge occurred in 40 (21%) patients in the transfusion group and 48 (26%) patients in the control group (risk difference -4·98% [95% CI -15·08 to 5·34]; relative risk 0·81 [95% CI 0·56 to 1·17]; p=0·16). 13 adverse events occurred in the transfusion group and two occurred in the control group (5·81% [-4·42 to 16·01]; 6·26 [1·43 to 27·34]; p=0·0064). Adverse events that were possibly, probably, or definitely related to transfusion included three cases of urticaria, one maculopapular rash, one pruritus, and one chest pain, as well as one case each of anaphylaxis, transfusion-related acute lung injury, and fluid overload that resulted in serious adverse events. No death was reported., Interpretation: In adult patients with dengue and thrombocytopenia, prophylactic platelet transfusion was not superior to supportive care in preventing bleeding, and might be associated with adverse events., Funding: National Medical Research Council, Singapore., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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41. Current Status of Dengue Therapeutics Research and Development.
- Author
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Low JG, Ooi EE, and Vasudevan SG
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antiviral Agents therapeutic use, Dengue prevention & control, Drug Discovery, Humans, Antibodies, Monoclonal pharmacology, Antiviral Agents pharmacology, Dengue drug therapy
- Abstract
Dengue is a significant global health problem. Even though a vaccine against dengue is now available, which is a notable achievement, its long-term protective efficacy against each of the 4 dengue virus serotypes remains to be definitively determined. Consequently, drugs directed at the viral targets or critical host mechanisms that can be used safely as prophylaxis or treatment to effectively ameliorate disease or reduce disease severity and fatalities are still needed to reduce the burden of dengue. This review will provide a brief account of the status of therapeutics research and development for dengue., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2017
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42. Dengue virus compartmentalization during antibody-enhanced infection.
- Author
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Ong EZ, Zhang SL, Tan HC, Gan ES, Chan KR, and Ooi EE
- Subjects
- Antigens, CD metabolism, Cell Line, Tumor, Dengue Virus physiology, Humans, Leukocyte Immunoglobulin-like Receptor B1 metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism, Virus Internalization, Antibody-Dependent Enhancement, Dengue immunology, Dengue Virus immunology, Phagosomes immunology
- Abstract
Secondary infection with a heterologous dengue virus (DENV) serotype increases the risk of severe dengue, through a process termed antibody-dependent enhancement (ADE). During ADE, DENV is opsonized with non- or sub-neutralizing antibody levels that augment entry into monocytes and dendritic cells through Fc-gamma receptors (FcγRs). We previously reported that co-ligation of leukocyte immunoglobulin-like receptor-B1 (LILRB1) by antibody-opsonized DENV led to recruitment of SH2 domain-containing phosphatase-1 (SHP-1) to dephosphorylate spleen tyrosine kinase (Syk) and reduce interferon stimulated gene induction. Here, we show that LILRB1 also signals through SHP-1 to attenuate the otherwise rapid acidification for lysosomal enzyme activation following FcγR-mediated uptake of DENV. Reduced or slower trafficking of antibody-opsonized DENV to lytic phagolysosomal compartments, demonstrates how co-ligation of LILRB1 also permits DENV to overcome a cell-autonomous immune response, enhancing intracellular survival of DENV. Our findings provide insights on how antiviral drugs that modify phagosome acidification should be used for viruses such as DENV.
- Published
- 2017
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43. Asymptomatic dengue infection may trigger Guillain-Barré syndrome.
- Author
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Umapathi T, Lim CS, Ooi EE, Zhang SL, Goh EJ, Tan HC, Chng KY, and Willison H
- Subjects
- Dengue epidemiology, Epidemics, Guillain-Barre Syndrome epidemiology, Humans, Singapore epidemiology, Dengue complications, Guillain-Barre Syndrome etiology
- Published
- 2016
- Full Text
- View/download PDF
44. Discovery of B-cell epitopes for development of dengue vaccines and antibody therapeutics.
- Author
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Anasir MI and Poh CL
- Subjects
- Antibodies, Neutralizing, Antibodies, Viral, Epitopes, B-Lymphocyte, Humans, Viral Envelope Proteins, Dengue prevention & control, Dengue Vaccines, Dengue Virus
- Abstract
Dengue is one of the most frequently transmitted viral infections globally which creates a serious burden to the healthcare system in many countries in the tropical and subtropical regions. To date, no vaccine has demonstrated balanced protection against the four dengue serotypes. Dengvaxia as the only vaccine that has been licensed for use in endemic areas has shown an increased risk in dengue-naïve vaccines to develop severe dengue. A crucial element in protection from dengue infection is the neutralizing antibody responses. Therefore, the identification of protective linear B-cell epitopes can guide vaccine design and facilitate the development of monoclonal antibodies as dengue therapeutics. This review summarizes the identification of dengue B-cell epitopes within the envelope (E) protein of dengue that can be incorporated into peptide vaccine constructs. These epitopes have been identified through approaches such as bioinformatics, three-dimensional structure analysis of antibody-dengue complexes, mutagenesis/alanine scanning and escape mutant studies. Additionally, the therapeutic potential of monoclonal antibodies targeting the E protein of dengue is reviewed. This can provide a basis for the design of future dengue therapies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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45. Phylodynamics of dengue virus 2 in Nicaragua leading up to the 2019 epidemic reveals a role for lineage turnover.
- Author
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Thongsripong P, Edgerton SV, Bos S, Saborío S, Kuan G, Balmaseda A, Harris E, and Bennett SN
- Subjects
- Humans, Child, Animals, Nicaragua epidemiology, Phylogeny, Cohort Studies, Dengue Virus genetics, Dengue epidemiology, Zika Virus, Zika Virus Infection
- Abstract
Background: Dengue is a mosquito-borne viral disease posing a significant threat to public health. Dengue virus (DENV) evolution is often characterized by lineage turnover, which, along with ecological and immunological factors, has been linked to changes in dengue phenotype affecting epidemic dynamics. Utilizing epidemiologic and virologic data from long-term population-based studies (the Nicaraguan Pediatric Dengue Cohort Study and Nicaraguan Dengue Hospital-based Study), we describe a lineage turnover of DENV serotype 2 (DENV-2) prior to a large dengue epidemic in 2019. Prior to this epidemic, Nicaragua had experienced relatively low levels of DENV transmission from 2014 to 2019, a period dominated by chikungunya in 2014/15 and Zika in 2016., Results: Our phylogenetic analyses confirmed that all Nicaraguan DENV-2 isolates from 2018 to 2019 formed their own clade within the Nicaraguan lineage of the Asian/American genotype. The emergence of the new DENV-2 lineage reflects a replacement of the formerly dominant clade presiding from 2005 to 2009, a lineage turnover marked by several shared derived amino acid substitutions throughout the genome. To elucidate evolutionary drivers of lineage turnover, we performed selection pressure analysis and reconstructed the demographic history of DENV-2. We found evidence of adaptive evolution by natural selection at the codon level as well as in branch formation., Conclusions: The timing of its emergence, along with a statistical signal of adaptive evolution and distinctive amino acid substitutions, the latest in the NS5 gene, suggest that this lineage may have increased fitness relative to the prior dominant DENV-2 strains. This may have contributed to the intensity of the 2019 DENV-2 epidemic, in addition to previously identified immunological factors associated with pre-existing Zika virus immunity., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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46. Dengue: updates for dermatologists on the world's fastest-growing vector-borne disease.
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Braun M, Andersen LK, Norton SA, and Coates SJ
- Subjects
- Humans, Dermatologists, Europe, Climate Change, Dengue diagnosis, Dengue epidemiology, Dengue therapy, Exanthema
- Abstract
Dengue is the world's fastest-growing vector borne disease and has significant epidemic potential in suitable climates. Recent disease models incorporating climate change scenarios predict geographic expansion across the globe, including parts of the United States and Europe. It will be increasingly important in the next decade for dermatologists to become familiar with dengue, as it commonly manifests with rashes, which can be used to aid diagnosis. In this review, we discuss dengue for general dermatologists, specifically focusing on its cutaneous manifestations, epidemiology, diagnosis, treatment, and prevention. As dengue continues to spread in both endemic and new locations, dermatologists may have a larger role in the timely diagnosis and management of this disease., (© 2023 the International Society of Dermatology.)
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- 2023
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47. Efficient reverse genetics approach involving infectious subgenomic amplicon for engineering dengue virus.
- Author
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Park CJ, Lee YA, Yoo SM, Kim GA, Lee MS, and Park C
- Subjects
- Humans, Reverse Genetics methods, Virus Replication genetics, Dengue Virus genetics, Flavivirus genetics, Flaviviridae genetics, Dengue
- Abstract
Dengue virus, which belongs to the Flaviviridae family, can induce a range of symptoms from mild to severe, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. While infectious cloning technology is a useful tool for understanding viral pathogenesis and symptoms, it exhibits limitations when constructing the entire Flavivirus genome. The instability and toxicity of the genome to bacteria make its full-length construction in bacterial vectors a time-consuming and laborious process. To address these challenges, we employed the modified infectious subgenomic amplicon (ISA) method in this study, which can potentially be a superior tool for reverse genetic studies on the dengue virus. Using ISA, we generated recombinant dengue viruses de novo and validated their robust replication in both human and insect cell lines, which was comparable to that of the original strains. Moreover, the efficiency of ISA in genetically modifying the dengue virus was elucidated by successfully inserting the gene for green fluorescence protein into the genome of dengue virus serotype 4. Overall, this study highlighted the effectiveness of ISA for genetically engineering the dengue virus and provided a technical basis for a convenient reverse genetics system that could expedite investigations into the dengue virus., (© 2023 Wiley Periodicals LLC.)
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- 2023
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48. Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients.
- Author
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Sung C, Wei Y, Watanabe S, Lee HS, Khoo YM, Fan L, Rathore AP, Chan KW, Choy MM, Kamaraj US, Sessions OM, Aw P, de Sessions PF, Lee B, Connolly JE, Hibberd ML, Vijaykrishna D, Wijaya L, Ooi EE, Low JG, and Vasudevan SG
- Subjects
- Adult, Antiviral Agents adverse effects, Cytokines blood, Dengue virology, Dengue Virus genetics, Dengue Virus isolation & purification, Dengue Virus physiology, Female, Half-Life, High-Throughput Nucleotide Sequencing, Humans, Indolizines adverse effects, Indolizines blood, Male, Phylogeny, Th1 Cells immunology, Viremia drug therapy, Virus Replication drug effects, Antiviral Agents administration & dosage, Antiviral Agents pharmacokinetics, Dengue drug therapy, Dengue immunology, Dengue Virus drug effects, Indolizines administration & dosage, Indolizines pharmacokinetics, Viral Load drug effects
- Abstract
Unlabelled: CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir's potential value for treatment of other flaviruses such as Zika virus should be investigated urgently., Trial Registration: ClinicalTrials.gov NCT01619969.
- Published
- 2016
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49. Discovery and Validation of Prognostic Biomarker Models to Guide Triage among Adult Dengue Patients at Early Infection.
- Author
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Pang J, Lindblom A, Tolfvenstam T, Thein TL, Naim AN, Ling L, Chow A, Chen MI, Ooi EE, Leo YS, and Hibberd ML
- Subjects
- Adult, Aged, Biomarkers metabolism, Case-Control Studies, Dengue classification, Dengue genetics, Dengue therapy, Early Diagnosis, Female, Gene Expression Profiling, Hospitalization, Humans, Male, Microarray Analysis, Middle Aged, Prognosis, Sensitivity and Specificity, Young Adult, Biomarkers analysis, Dengue diagnosis, Triage methods
- Abstract
Background: Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1-3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring., Methods: RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005-2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009-2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC)., Results: The WS+Hosp group had significantly higher viral load (P<0.001), lower platelet (P<0.001) and lymphocytes counts (P = 0.004) at early infection compared to the Non-WS+Non-Hosp group. From the RNA microarray and protein assays, the top single RNA and protein prognostic models at early infection were CCL8 RNA (AUC:0.73) and IP-10 protein (AUC:0.74), respectively. The model with CCL8, VPS13C RNA, uPAR protein, and with CCL8, VPS13C RNA and platelets were the best biomarker models for stratifying adult dengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively., Conclusions: At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here based on these pathophysiology differences, could offer earlier and complementary indicators to the clinical WHO 2009 WS guide, in order to triage adult dengue patients at early infection.
- Published
- 2016
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50. Dengue Disease Modelling and Forecasting: Utility and Limitations.
- Author
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Kalimuddin S, Low JG, and Ooi EE
- Subjects
- Forecasting, Health Planning, Humans, Models, Theoretical, Singapore epidemiology, Dengue epidemiology, Epidemics
- Published
- 2016
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