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Base Distribution in Dengue Nucleotide Sequences Differs Significantly from Other Mosquito-Borne Human-Infecting Flavivirus Members.

Artigo em Inglês | MEDLINE | ID: mdl-30062973


Among the mosquito-borne human-infecting flavivirus species that include Zika, West Nile, yellow fever, Japanese encephalitis and Dengue viruses, the Zika virus is found to be closest to Dengue virus, sharing the same clade in the Flavivirus phylogenetic tree. We consider these five flaviviruses and on closer examination in our analyses, the nucleotide sequences of the Dengue viral genes (envelope and NS5) and genomes are seen to be quite widely different from the other four flaviviruses. We consider the extent of this distinction and determine the advantage and/or disadvantage such differences may confer upon the Dengue viral pathogenesis. We have primarily used a 2D graphical representation technique to show the differences in base distributions in these five flaviviruses and subsequently, obtained quantitative estimates of the differences. Similarity/dissimilarity between the viruses based on the genes were also determined which showed that the differences with the Dengue genes are more pronounced. We found that the Dengue viruses compared to the other four flaviviruses spread rapidly worldwide and became endemic in various regions with small alterations in sequence composition relative to the host populations as revealed by codon usage biases and phylogenetic examination. We conclude that the Dengue genes are indeed more widely separated from the other aforementioned mosquito-borne human-infecting flaviviruses due to excess adenine component, a feature that is sparse in the literature. Such excesses have a bearing on drug and vaccine, especially peptide vaccine, development and should be considered appropriately.

Platelet Transfusion Related Panophthalmitis and Endophthalmitis in Patients with Dengue Hemorrhagic Fever.

Am J Trop Med Hyg; 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30062992


Dengue is a vector-borne viral illness of major public health importance. It is endemic in many parts of India and also causes frequent epidemics. Platelet transfusions are given in severe cases of dengue fever to treat and prevent hemorrhagic complications. Here, we report three patients in North India with development of panophthalmitis and endophthalmitis shortly after receiving platelet transfusion.

Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach.

Expert Rev Vaccines; : 1-11, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30063839


BACKGROUND: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination. RESEARCH DESIGN AND METHODS: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study. The model was used to assess vaccination outcomes for a range of transmission settings over 5-30 years, with or without indirect protection. MAIN OUTCOME MEASURES: Symptomatic dengue cases, dengue hospitalizations, and severe dengue cases. RESULTS: The model is consistent with previous results indicating a transitory period at increased risk for dengue-seronegative vaccine recipients (setting-dependent duration) and long-term benefits for dengue-seropositive recipients. At the population level, benefits to seropositive individuals over 10 years outweighed the risk to those seronegative in moderate to high transmission settings (≥50% seropositivity at age 9), especially in high transmission settings (no excess hospitalizations in dengue-seronegative for ≥80% seropositivity at age 9). Results were more favorable when longer time horizons or indirect protection were considered. CONCLUSIONS: Results indicate a public health benefit associated with dengue vaccination especially in high-transmission settings, even with the initial excess risks to dengue-seronegative patients which diminish over time.

DNA Switch: Toehold-Mediated DNA Isothermal Amplification for Dengue Serotyping.

SLAS Discov; : 2472555218791743, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30063871


The inherent ability of nucleic acids to recognize a complementary pair has gained wide popularity in DNA sensor applications. DNA molecules can be produced in bulk and easily incorporated with various nanomaterials for sensing applications. More complex designs and sophisticated DNA sensors have been reported over the years to allow DNA detection in a faster, cheaper, and more convenient manner. Here, we report a DNA sensor designed to function like a switch to turn "on" silver nanocluster (AgNC) generation in the presence of a specific DNA target. By defining the probe region sequence, we are able to tune the color of the AgNC generated in direct relation to the different targets. As a proof of concept, we used dengue RNA-dependent RNA polymerase conserved sequences from all four serotypes as targets. This method was able to distinguish each dengue serotype by generating the serotype-respective AgNCs. The DNA switch was also able to identify and amplify the correct target in a mixture of targets with good specificity. This strategy has a detection limit of between 1.5 and 2.0 µM depending on the sequence of AgNC. The DNA switch approach provides an attractive alternative for single-target or multiplex DNA detection.

Host-vector interaction in dengue: a simple mathematical model

Ceylon Med J; 63(2): 58-64, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-30064169


Introduction: Dengue is a mosquito-borne viral infection endemic in tropical and subtropical regions, now spreading at epidemic proportions causing a major health issue in Sri Lanka and elsewhere. No effective vaccine or a curative antiviral drug is available to prevent or treat the disease. The only way of mitigating dengue at present, is through mosquito eradication and educating the public on preventive measures which can minimizing the cycle of transfer. Objectives: A theoretical model of dengue with simple mathematics is presented to gain a quantitative understanding of the pattern of dengue outbreaks in Sri Lanka and suggest control measures. Methods: The statistics on incidence of the disease reported by the Epidemiology Unit is analyzed using the model. Despite simplicity, the model possesses explanatory and predictive capacity, enabling determination of crucial parameters. The model shows that the "infectives" increase exponentially in an outbreak, provided the number of vectors per human exceeds a threshold, illustrating not only vector eradication but measures which minimize their biting frequency and preventing prolonged survival are effective safeguards. Results: In a population consisting of 75% who are susceptible, the threshold is estimated to be 20 mosquitos per person. Conclusions: The model showed that the endemic equilibrium of the system can occur at any level. As demographic changes escalate mosquito breeding, they infect more and more susceptible people. The consequent increase in virus replication induces new strains broadening the genetic diversity of the virus and helping it to overcome the human immune response. The increasing endemicity of dengue due to this is demonstrated by the model.

Estimating dengue incidence and hospitalization in Malaysia, 2001 to 2013.

BMC Public Health; 18(1): 946, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30068318


BACKGROUND: Epidemiologic measures of the dengue burden such as prevalence and incidence are important for policy-making and monitoring the progress of disease control. It is a common practice where epidemiologic and economic research estimate dengue burden based on notification data. However, a basic challenge in estimating the incidence of dengue is that a significant proportion of infected population are asymptomatic. It can be overcome by using mathematical models that relate observed prevalence and mortality to incidence. In this study, we estimate the trend of dengue incidence and hospitalization in Malaysia. METHODS: This study is based entirely on the available secondary data sources on dengue in Malaysia. The age-specific incidence of dengue between 2001 and 2013 was estimated using the prevalence and mortality estimates in an incidence-prevalence-mortality (IPM) model. Data on dengue prevalence were extracted from six sero-surveys conducted in Malaysia between 2001 and 2013; while statistics on dengue notification and Case Fatality Rate were derived from National Dengue Surveillance System. Dengue hospitalization data for the years 2009 to 2013 were extracted from the Health Informatics Centre and the volumes of dengue hospitalization for hospitals with missing data were estimated with Poisson models. RESULTS: The dengue incidence in Malaysia varied from 69.9 to 93.4 per 1000 population (pkp) between 2001 and 2013.The temporal trend in incidence rate was decreasing since 2001. It has been reducing at an average rate of 2.57 pkp per year from 2001 to 2013 (p = 0.011). The age-specific incidence of dengue decreased steadily with dengue incidence reaching zero by age > 70 years. Dengue notification rate has remained stable since 2001 and the number of notified cases each year was only a small fraction of the incident cases (0.7 to 2.3%). Similarly, the dengue hospitalization was larger but still a small fraction of the incident cases (3.0 to 5.6%). CONCLUSION: Dengue incidence can be estimated with the use of sero-prevalence surveys and mortality data. This study highlights a reducing trend of dengue incidence in Malaysia and demonstrates the discrepancy between true dengue disease burden and cases reported by national surveillance system. Sero-prevalence studies with representative samples should be conducted regularly to allow better estimation of dengue burden in Malaysia.

Single amino acid mutation in dengue virus NS4B protein has opposing effects on viral proliferation in mammalian and mosquito cells.

Jpn J Infect Dis; 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30068888


Dengue virus (DENV) has a considerable impact on global health and causes morbidity and mortality each year. Through the passages of a DENV2 in BHK-21 cells, we have isolated a mutant clone of DENV2 which reveals cytopathic effects (CPE) rapidly compared to the parent strain in BHK-21 cells. To investigate the relationship between amino acid mutations and proliferation activity of the isolated DENV2 clone, we performed full genome sequencing and identified three amino acid mutations in its coding region, the Envelope (Env) T120K, NS4A M85T and NS4B G124A, compared to that of the parent strain. Genetically-modified recombinant DENV2 (rDENV2) carrying the NS4A M85T and NS4B G124A mutations produced higher titers of progeny virus in BHK-21, Vero and Huh-7 cells compared to wild-type (WT) rDENV2. Surprisingly, rDENV2 with mutations at NS4A M85T and NS4B G124A did not produce any plaques in C6/36 mosquito cell lines. Furthermore, rDENV2 possessing only the NS4B G124A mutation did not produce any plaques in C6/36 cells; however, it had higher viral titers in Vero and Huh-7 cells compared to WT rDENV2. Our results clearly showed that the DENV2 NS4B G124A mutation has opposing effects on viral proliferation in certain mammalian cells and mosquito cells.

T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses.

MBio; 9(4)2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087165


The 2015-2016 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrated that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping geographic distributions and have significant sequence similarities that can increase the potential for antibody and T cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent assays (ELISAs), we determined the serostatus of individuals living in a region of DENV and ZIKV endemicity in Brazil, identifying individuals with primary DENV (pDENV) and primary ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections; the presence of pDENV and pZIKV was further confirmed by neutralization tests. Development of an enzyme-linked immunosorbent spot (ELISPOT) assay for DENV and ZIKV structural and nonstructural (NS) protein antigens enabled us to distinguish infections by these viruses based on T cell responses and to characterize those responses. We found that gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) T cell responses to NS3 differentiated DENV and ZIKV infections with 94% sensitivity and 92% specificity. In general, we also showed that pDENV and sDENV cases and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns and that HIV-infected individuals show T cell responses that are lower than those shown by HIV-negative individuals. These results have important implications for DENV and ZIKV diagnostic and vaccine development and provide critical insights into the T cell response in individuals with multiple flaviviral infections. The potential for antibody and T cell cross-reactions to DENV and ZIKV, flaviviruses that cocirculate and can sequentially infect individuals, has complicated diagnostic and vaccine development. Our serological data show that antibodies to nonstructural protein 1 can distinguish sequential human infections by DENV and ZIKV. The development of a simple and inexpensive assay also enables the differentiation of DENV and ZIKV infections based on characterization of T cell responses. Our T cell data reveal strong response patterns that are similar in nature to those seen with individuals with one or multiple DENV infections and with individuals with only primary ZIKV infection and ZIKV-infected individuals with previous DENV exposure. The characterization of T cell responses in a serologically validated group of individuals is of relevance to the development of vaccines and immunotherapeutics against these global threats.

The role of lipids in the inception, maintenance and complications of dengue virus infection.

Sci Rep; 8(1): 11826, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087415


Dengue fever is a viral condition that has become a recurrent issue for public health in tropical countries, common endemic areas. Although viral structure and composition have been widely studied, the infection phenotype in terms of small molecules remains poorly established. This contribution providing a comprehensive overview of the metabolic implications of the virus-host interaction using a lipidomic-based approach through direct-infusion high-resolution mass spectrometry. Our results provide further evidence that lipids are part of both the immune response upon Dengue virus infection and viral infection maintenance mechanism in the organism. Furthermore, the species described herein provide evidence that such lipids may be part of the mechanism that leads to blood-related complications such as hemorrhagic fever, the severe form of the disease.

Endogenous gene selection for relative quantification PCR and IL6 transcript levels in the PBMC's of severe and non-severe dengue cases.

BMC Res Notes; 11(1): 550, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30071880


OBJECTIVES: Dengue viral infection ranges from dengue fever to dengue haemorrhagic fever and lethal dengue shock syndrome. Currently no means are available to monitor the progression of disease. Real time PCR based gene expression analyses are used to find potential molecular markers for effective prediction of dengue clinical outcome. The accuracy of qPCR analysis is strongly dependent on transcript normalization using stably expressed endogenous genes, which if selected imprecisely can lead to misinterpreted results. We aimed to determine the best fit for endogenous gene among six genes namely COX, ACTB, GAPDH, HMBS, HPRT and B2M for dengue viral infection cases. Gene stability was inferred from qPCR data by normalizing with two algorithms geNorm and Normfinder and the rankings generated were validated by gene expression analysis against target gene IL-6. RESULTS: Both the algorithms showed ACTB, HPRT, GAPDH as most stable genes. Normalizing with the stable genes revealed a significant fold change (p < .05) in IL-6 levels of .32, .52, .69, and .62 in non-dengue febrile illness, non severe, severe and All Dengue groups respectively compared to healthy controls. based on our study, we suggest ACTB with HPRT/GAPDH combination for normalization in qPCR for precise quantification of transcripts in dengue infected studies.

Estimating dengue under-reporting in Puerto Rico using a multiplier model.

PLoS Negl Trop Dis; 12(8): e0006650, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30080848


Dengue is a mosquito-borne viral illness that causes a variety of health outcomes, from a mild acute febrile illness to potentially fatal severe dengue. Between 2005 and 2010, the annual number of suspected dengue cases reported to the Passive Dengue Surveillance System (PDSS) in Puerto Rico ranged from 2,346 in 2006 to 22,496 in 2010. Like other passive surveillance systems, PDSS is subject to under-reporting. To estimate the degree of under-reporting in Puerto Rico, we built separate inpatient and outpatient probability-based multiplier models, using data from two different surveillance systems-PDSS and the enhanced dengue surveillance system (EDSS). We adjusted reported cases to account for sensitivity of diagnostic tests, specimens with indeterminate results, and differences between PDSS and EDSS in numbers of reported dengue cases. In addition, for outpatients, we adjusted for the fact that less than 100% of medical providers submit diagnostic specimens from suspected cases. We estimated that a multiplication factor of between 5 (for 2010 data) to 9 (for 2006 data) must be used to correct for the under-reporting of the number of laboratory-positive dengue inpatients. Multiplication factors of between 21 (for 2010 data) to 115 (for 2008 data) must be used to correct for the under-reporting of laboratory-positive dengue outpatients. We also estimated that, after correcting for underreporting, the mean annual rate, for 2005-2010, of medically attended dengue in Puerto Rico to be between 2.1 (for dengue inpatients) to 7.8 (for dengue outpatients) per 1,000 population. These estimated rates compare to the reported rates of 0.4 (dengue outpatients) to 0.1 (dengue inpatients) per 1,000 population. The multipliers, while subject to limitations, will help public health officials correct for underreporting of dengue cases, and thus better evaluate the cost-and-benefits of possible interventions.

Stratified sero-prevalence revealed overall high disease burden of dengue but suboptimal immunity in younger age groups in Pune, India.

PLoS Negl Trop Dis; 12(8): e0006657, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30080850


BACKGROUND: In India, dengue disease is emerging as the most important vector borne public health problem due to rapid and unplanned urbanization, high human density and week management of the disease. Clinical cases are grossly underreported and not much information is available on prevalence and incidence of the disease. METHODOLOGY: A cross sectional, stratified, facility based, multistage cluster sampling was conducted between May 4 and June 27, 2017 in Pune city. A total of 1,434 participants were enrolled. The serum samples were tested for detection of historical dengue IgG antibodies by ELISA using the commercial Panbio Dengue IgG Indirect ELISA kit. Anti-dengue IgG-capture Panbio ELISA was used for detection of high titered antibodies to detect recent secondary infection. We used this data to estimate key transmission parameters like force of infection and basic reproductive number. A subset of 120 indirect ELISA positive samples was also tested for Plaque Reduction Neutralizing Antibodies for determining serotype-specific prevalence. FINDINGS: Overall, 81% participants were infected with dengue virus (DENV) at least once if not more. The positivity was significantly different in different age groups. All the adults above 70 years were positive for DENV antibodies. Over 69% participants were positive for neutralizing antibodies against all 4 serotypes suggesting intense transmission of all DENV serotypes in Pune. Age-specific seroprevalence was consistent with long-term, endemic circulation of DENV. There was an increasing trend with age, from 21.6% among <36 months to 59.4% in age group 10-12 years. We estimate that 8.68% of the susceptible population gets infected by DENV each year resulting into more than 3,00,000 infections and about 47,000 to 59,000 cases per year. This transmission intensity is similar to that reported from other known hyper-endemic settings in Southeast Asia and the Americas but significantly lower than report from Chennai. CONCLUSIONS: Our study suggests that Pune city has high disease burden, all 4 serotypes are circulating, significant spatial heterogeneity in seroprevalence and suboptimal immunity in younger age groups. This would allow informed decisions to be made on management of dengue and introduction of upcoming dengue vaccines in the city.

Prediction of dengue outbreaks in Mexico based on entomological, meteorological and demographic data.

PLoS One; 13(8): e0196047, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30080868


Dengue virus has shown a complex pattern of transmission across Latin America over the last two decades. In an attempt to explain the permanence of the disease in regions subjected to drought seasons lasting over six months, various hypotheses have been proposed. These include transovarial transmission, forest reservoirs and asymptomatic human virus carriers. Dengue virus is endemic in Mexico, a country in which half of the population is seropositive. Seropositivity is a risk factor for Dengue Hemorrhagic Fever upon a second encounter with the dengue virus. Since Dengue Hemorrhagic Fever can cause death, it is important to develop epidemiological mathematical tools that enable policy makers to predict regions potentially at risk for a dengue epidemic. We formulated a mathematical model of dengue transmission, considering both human behavior and environmental conditions pertinent to the transmission of the disease. When data on past human population density, temperature and rainfall were entered into this model, it provided an accurate picture of the actual spread of dengue over recent years in four states (representing two climactic conditions) in Mexico.

Analysis of a Dengue Model with Vertical Transmission and Application to the 2014 Dengue Outbreak in Guangdong Province, China.

Bull Math Biol; 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30083966


There is evidence showing that vertical transmission of dengue virus exists in Aedes mosquitoes. In this paper, we propose a deterministic dengue model with vertical transmission in mosquitoes by including aquatic mosquitoes (eggs, larvae and pupae), adult mosquitoes (susceptible, exposed and infectious) and human hosts (susceptible, exposed, infectious and recovered). We first analyze the existence and stability of disease-free equilibria, calculate the basic reproduction number and discuss the existence of the disease-endemic equilibrium. Then, we study the impact of vertical transmission of the virus in mosquitoes on the spread dynamics of dengue. We also use the model to simulate the reported infected human data from the 2014 dengue outbreak in Guangdong Province, China, carry out sensitivity analysis of the basic reproduction number in terms of the model parameters, and seek for effective control measures for the transmission of dengue virus.

Co-circulation of four dengue serotypes at South Eastern Andhra Pradesh, India: A prospective study.

Indian J Med Microbiol; 36(2): 236-240, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30084417


Background: Dengue is one of the most important mosquito-borne viral diseases in the world. The emergence and spread of four dengue viruses (DENVs) (serotypes) represent a global pandemic. The four distinct serotypes are, namely, DENV-1, DENV-2, DENV-3 and DENV-4. Very few dengue serotyping studies have been reported from Andhra Pradesh. In this context, the present study focuses on the circulating serotypes of dengue in South-Eastern Andhra Pradesh. Methodology: Study was done at Sri Venkateswara Institute of Medical Sciences, a teaching hospital in Tirupati, Andhra Pradesh. Acute phase dengue serum samples were collected and tested for NS1 antigen and anti-human IgM antibodies by enzyme-linked immunosorbent assay (ELISA). NS1-positive samples were further serotyped by reverse transcriptase real-time polymerase chain reaction (rRT-PCR). Results: A total of 398 serum samples were received from clinically suspected dengue fever cases. Of these, 150 (37.7%) samples were positive for NS1 and/or IgM ELISA. The 96 NS1 antigen-positive samples were further processed for serotyping, of which 36 were negative by rRT-PCR. DENV-2 (41%) was the predominant serotype, followed by DENV-4 (37%), DENV-3 (12%) and DENV-1 (10%) in descending order. Conclusion: This study reports the all four dengue serotypes' co-circulation. This is the first report from South Eastern Andhra Pradesh. Amongst four, DENV-2 was predominant followed by DENV-4. The information of predominant serotypes can guide in forecasting dengue outbreaks and improving control measures of vectors thus may be helpful in the prevention of outbreaks.

Identification of prevalent dengue serotypes by reverse transcriptase polymerase chain reaction and correlation with severity of dengue as per the recent World Health Organization classification (2009).

Indian J Med Microbiol; 36(2): 273-278, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30084423


Context: A definite link between distinct dengue serotypes and severe clinical manifestations has not been established yet. The WHO classification (2009) of dengue is more competent in diagnosing severe cases compared to traditional (1997) classification. Aims: This study aimed to identify prevalent dengue serotypes and to correlate the severity of dengue with the dengue virus (DENV) serotypes in target population as per the recent WHO classification (2009). Settings and Design: A retrospective comparative observational study was conducted from 1 January 2015 to 31 December 2015. Subjects and Methods: We tested 242 dengue NS-1 antigen ELISA-positive cases for serotyping by dengue reverse transcriptase-polymerase chain reaction (RT-PCR). Severity of each dengue case confirmed by RT-PCR was determined as per the recent WHO classification (2009). Results: On the basis of RT-PCR, dengue infection was confirmed in 135 (55.78%) patients. DEN-3 was the most common serotype found in 71 (52.6%) patients, followed by DEN-2 serotype with 44 (32.6%) patients. Nearly 2.22% cases of DEN-2 and 2.96% cases of DEN-3 serotype were having dengue with warning signs. Severe dengue was found in 2.22% cases of DEN-2 and 5.18% cases of DEN-3 serotypes. Thrombocytopenia, haemorrhagic manifestations and atypical presentations were found most commonly in DEN-3 followed by DEN-2 serotype. Coinfection with more than one serotype was observed in our study, with the most common coinfection pattern being DEN-2 and DEN-3 serotypes. Conclusions: DENV-3 and DENV-2 serotypes are prevalent in the region and are associated with a more serious clinical profile than other serotypes.
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