Showing papers on "Dengue fever published in 2005"
TL;DR: The structural organization of these viruses and their associated structural proteins has provided insight into the molecular transitions that occur during the viral life cycle, such as assembly, budding, maturation and fusion.
Abstract: Dengue, Japanese encephalitis, West Nile and yellow fever belong to the Flavivirus genus, which is a member of the Flaviviridae family. They are human pathogens that cause large epidemics and tens of thousands of deaths annually in many parts of the world. The structural organization of these viruses and their associated structural proteins has provided insight into the molecular transitions that occur during the viral life cycle, such as assembly, budding, maturation and fusion. This review focuses mainly on structural studies of dengue virus.
1,167 citations
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TL;DR: This review summarizes the current approaches to establishing the diagnosis, managing the complications, and preventing this potentially dangerous infection.
Abstract: Dengue infection may be the most common infection other than malaria among travelers to tropical areas. This flavivirus infection is transmitted by mosquitoes. Although it often is asymptomatic, dengue infection can lead to leukopenia, thrombocytopenia, and even hemorrhagic complications and shock. This review summarizes the current approaches to establishing the diagnosis, managing the complications, and preventing this potentially dangerous infection.
438 citations
TL;DR: The crystal structure of a soluble fragment of the envelope glycoprotein E from dengue virus type 3 is determined and shows that neighboring glycans on the viral surface are spaced widely enough that they can interact with multiple carbohydrate recognition domains on oligomeric lectins such as DC-SIGN, ensuring maximum affinity for these putative receptors.
Abstract: Dengue virus is an emerging global health threat. The major envelope glycoprotein, E, mediates viral attachment and entry by membrane fusion. Antibodies that bind but fail to neutralize noncognate serotypes enhance infection. We have determined the crystal structure of a soluble fragment of the envelope glycoprotein E from dengue virus type 3. The structure closely resembles those of E proteins from dengue type 2 and tick-borne encephalitis viruses. Serotype-specific neutralization escape mutants in dengue virus E proteins are all located on a surface of domain III, which has been implicated in receptor binding. While antibodies against epitopes in domain I are nonneutralizing in dengue virus, there are neutralizing antibodies that recognize serotype-conserved epitopes in domain II. The mechanism of neutralization for these antibodies is probably inhibition of membrane fusion. Our structure shows that neighboring glycans on the viral surface are spaced widely enough (at least 32 A) that they can interact with multiple carbohydrate recognition domains on oligomeric lectins such as DC-SIGN, ensuring maximum affinity for these putative receptors.
423 citations
TL;DR: This serotype-specific, fourplex real-time reverse transcriptase PCR nucleic acid detection assay can be used as a method for differential diagnosis of a specific DEN serotype in viremic dengue patients and as a tool for rapid identification and serotyping of DEN virus isolates.
Abstract: The dengue (DEN) viruses are positive-strand RNA viruses in the genus Flavivirus. Dengue fever and dengue hemorrhagic fever/dengue shock syndrome are important human arboviral diseases caused by infection with one of four closely related but serologically distinct DEN viruses, designated DEN-1, DEN-2, DEN-3, and DEN-4 viruses. All four DEN serotypes are currently co-circulating throughout the subtropics and tropics, and genotypic variation occurs among isolates within a serotype. A real-time quantitative nucleic acid amplification assay has been developed to detect viral RNA of a single DEN virus serotype. Each primer-probe set is DEN serotype specific, yet detects all genotypes in a panel of 7 to 10 representative isolates of a serotype. In single reactions and in fourplex reactions (containing four primer-probe sets in a single reaction mixture), standard dilutions of virus equivalent to 0.002 PFU of DEN-2, DEN-3, and DEN-4 viruses were detected; the limit of detection of DEN-1 virus was 0.5 equivalent PFU. Singleplex and fourplex reactions were evaluated in a panel of 40 viremic serum specimens with 10 specimens per serotype, containing 0.002 to 6,000 equivalent PFU/reaction (0.4 to 1.2 x 10(6) PFU/ml). Viral RNA was detected in all viremic serum specimens in singleplex and fourplex reactions. Thus, this serotype-specific, fourplex real-time reverse transcriptase PCR nucleic acid detection assay can be used as a method for differential diagnosis of a specific DEN serotype in viremic dengue patients and as a tool for rapid identification and serotyping of DEN virus isolates.
408 citations
TL;DR: It is demonstrated that RT-LAMP assay has the potential clinical application for detection and differentiation of dengue virus serotypes, especially in developing countries.
Abstract: The development and validation of a one-step, real-time, and quantitative dengue virus serotype-specific reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay targeting the 3′ noncoding region for the rapid detection and differentiation of dengue virus serotypes are reported. The RT-LAMP assay is very simple and rapid, wherein the amplification can be obtained in 30 min under isothermal conditions at 63°C by employing a set of four serotype-specific primer mixtures through real-time monitoring in an inexpensive turbidimeter. The evaluation of the RT-LAMP assay for use for clinical diagnosis with a limited number of patient serum samples, confirmed to be infected with each serotype, revealed a higher sensitivity by picking up 100% samples as positive, whereas 87% and 81% of the samples were positive by reverse transcription-PCR and virus isolation, respectively. The sensitivity and specificity of the RT-LAMP assay for the detection of viral RNA in patient serum samples with reference to virus isolation were 100% and 93%, respectively. The optimal assay conditions with zero background and no cross-reaction with other closely related members of the Flavivirus family (Japanese encephalitis, West Nile, and St. Louis encephalitis viruses) as well as within the four serotypes of dengue virus were established. None of the serum samples from healthy individuals screened in this study showed any cross-reaction with the four dengue virus serotype-specific RT-LAMP assay primers. These findings demonstrate that RT-LAMP assay has the potential clinical application for detection and differentiation of dengue virus serotypes, especially in developing countries.
349 citations
TL;DR: Age-related differences were identified in the prevalence of specific clinical manifestations as well as in their association with a confirmed DEN diagnosis of dengue virus infections in Nicaragua.
Abstract: To investigate age-related differences in dengue severity, 114 infants, 1,211 children, and 346 adults with laboratory-confirmed dengue virus (DEN) infections presenting to three hospitals in major urban centers in Nicaragua were recruited from 1999 to 2001. The age distribution of dengue cases and the circulating serotype (predominantly DEN2) were representative of national data. Similar results were obtained when either dengue hemorrhagic fever/dengue shock syndrome or its principal manifestations (vascular permeability, internal hemorrhage, marked thrombocytopenia, and/or shock) were analyzed in relation to age and immune status. The burden of disease and of severe dengue was found predominantly in infants 4–9 months of age and in children 5–9 years old, and secondary DEN infection was a risk factor for severity in children. Age-related differences were identified in the prevalence of specific clinical manifestations as well as in their association with a confirmed DEN diagnosis. This represents one of the few comprehensive studies to analyze characteristics of dengue in infants, children, and adults in the same population and highlights age-related differences in dengue severity.
333 citations
TL;DR: This outbreak underscores the importance of maintaining surveillance and control of potential disease vectors even in the absence of an imminent disease threat.
Abstract: Autochthonous dengue infections were last reported in Hawaii in 1944. In September 2001, the Hawaii Department of Health was notified of an unusual febrile illness in a resident with no travel history; dengue fever was confirmed. During the investigation, 1,644 persons with locally acquired denguelike illness were evaluated, and 122 (7%) laboratory-positive dengue infections were identified; dengue virus serotype 1 was isolated from 15 patients. No cases of dengue hemorrhagic fever or shock syndrome were reported. In 3 instances autochthonous infections were linked to a person who reported denguelike illness after travel to French Polynesia. Phylogenetic analyses showed the Hawaiian isolates were closely associated with contemporaneous isolates from Tahiti. Aedes albopictus was present in all communities surveyed on Oahu, Maui, Molokai, and Kauai; no Ae. aegypti were found. This outbreak underscores the importance of maintaining surveillance and control of potential disease vectors even in the absence of an imminent disease threat.
320 citations
TL;DR: A specific and sensitive ChIKV one-step TaqMan RT-PCR assay was developed as a tool for the diagnosis of African CHIKV as a rapid indicator of active infection by quantifying viral load and showed that a simple heat viral RNA release during the reverse transcription step constituted an alternative to the conventional RNA extraction method.
310 citations
TL;DR: The results indicate that CD209 has a crucial role in dengue pathogenesis, which discriminates between severe d Dengue fever and denge hemorrhagic fever, which may have consequences for therapeutic and preventive strategies.
Abstract: Dengue fever and dengue hemorrhagic fever are mosquito-borne viral diseases. Dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN1, encoded by CD209), an attachment receptor of dengue virus, is essential for productive infection of dendritic cells. Here, we report strong association between a promoter variant of CD209, DCSIGN1-336, and risk of dengue fever compared with dengue hemorrhagic fever or population controls. The G allele of the variant DCSIGN1-336 was associated with strong protection against dengue fever in three independent cohorts from Thailand, with a carrier frequency of 4.7% in individuals with dengue fever compared with 22.4% in individuals with dengue hemorrhagic fever (odds ratio for risk of dengue hemorrhagic fever versus dengue fever: 5.84, P = 1.4 x 10(-7)) and 19.5% in controls (odds ratio for protection: 4.90, P = 2 x 10(-6)). This variant affects an Sp1-like binding site and transcriptional activity in vitro. These results indicate that CD209 has a crucial role in dengue pathogenesis, which discriminates between severe dengue fever and dengue hemorrhagic fever. This may have consequences for therapeutic and preventive strategies.
301 citations
TL;DR: Brazil has experienced an increase in dengue disease severity in the past 5 years, according to a report by the World Health Organization.
Abstract: In the last 5 years, Brazil has accounted for ≈70% of reported dengue fever cases in the Americas. We analyzed trends of dengue and dengue hemorrhagic fever (DHF) from the early 1980s to 2002 by using surveillance data from the Brazilian Ministry of Health. Two distinct epidemiologic patterns for dengue were observed: localized epidemics (1986–1993), and endemic and epidemic virus circulation countrywide (1994–2002). Currently, serotypes 1, 2, and 3 cocirculate in 22 of 27 states. Dengue and DHF affected mainly adults; however, an increase in occurrence of DHF among children has been recently detected in northern Brazil, which suggests a shift in the occurrence of severe disease to younger age groups. In 2002, hospitalizations increased, which points out the change in disease severity compared to that seen in the 1990s. We describe the epidemiology of dengue in Brazil, characterizing the changing patterns of it and DHF during the last 20 years.
278 citations
TL;DR: It is shown that in replicon-containing cells dengue virus RNA replication and the replication of encephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviral effects ofIFN-α.
Abstract: Alpha/beta interferon (IFN-alpha/beta) is a key mediator of innate antiviral responses but has little effect on the established replication of dengue viruses, which are mosquito-borne flaviviruses of immense global health importance. Understanding how the IFN system is inhibited in dengue virus-infected cells would provide critical insights into disease pathogenesis. In a recent study analyzing the ability of individual dengue virus-encoded proteins to antagonize the IFN response, nonstructural (NS) protein 4B and possibly NS2A and NS4A were identified as candidate IFN antagonists. In monkey cells, NS4B appeared to inhibit both the IFN-alpha/beta and IFN-gamma signal transduction pathways, which are distinct but overlapping (J. L. Munoz-Jordan, G. G. Sanchez-Burgos, M. Laurent-Rolle, and A. Garcia-Sastre, Proc. Natl. Acad. Sci. USA 100:14333-14338, 2003). For this study, we examined the effects of dengue virus on the human IFN system, using cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and that expressed all of the dengue virus nonstructural proteins together. We show here that in replicon-containing cells dengue virus RNA replication and the replication of encephalomyocarditis virus, an IFN-sensitive virus, are resistant to the antiviral effects of IFN-alpha. The presence of dengue virus replicons reduces global IFN-alpha-stimulated gene expression and specifically inhibits IFN-alpha but not IFN-gamma signal transduction. In cells containing replicons or infected with dengue virus, we found reduced levels of signal transducer and activator of transcription 2 (STAT2), which is a key component of IFN-alpha but not IFN-gamma signaling. Collectively, these data show that dengue virus is capable of subverting the human IFN response by down-regulating STAT2 expression.
TL;DR: It is suggested that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.
Abstract: Previous studies have suggested that α-glucosidase inhibitors such as castanospermine and deoxynojirimycin inhibit dengue virus type 1 infection by disrupting the folding of the structural proteins prM and E, a step crucial to viral secretion. We extend these studies by evaluating the inhibitory activity of castanospermine against a panel of clinically important flaviviruses including all four serotypes of dengue virus, yellow fever virus, and West Nile virus. Using in vitro assays we demonstrated that infections by all serotypes of dengue virus were inhibited by castanospermine. In contrast, yellow fever virus and West Nile virus were partially and almost completely resistant to the effects of the drug, respectively. Castanospermine inhibited dengue virus infection at the level of secretion and infectivity of viral particles. Importantly, castanospermine prevented mortality in a mouse model of dengue virus infection, with doses of 10, 50, and 250 mg/kg of body weight per day being highly effective at promoting survival (P ≤ 0.0001). Correspondingly, castanospermine had no adverse or protective effect on West Nile virus mortality in an analogous mouse model. Overall, our data suggest that castanospermine has a strong antiviral effect on dengue virus infection and warrants further development as a possible treatment in humans.
TL;DR: This is the first report of a longitudinal cohort study of naturally acquired DF and DHF in adults in adults and Dengue-2 virus was the predominant serotype identified, but all four serotypes were detected among the cohort.
Abstract: A prospective study of dengue fever (DF) and dengue hemorrhagic fever (DHF) was conducted in a cohort of adult volunteers from two textile factories located in West Java, Indonesia. Volunteers in the cohort were bled every three months and were actively followed for the occurrence of dengue (DEN) disease. The first two years of the study showed an incidence of symptomatic DEN disease of 18 cases per 1,000 person-years and an estimated asymptomatic/ mild infection rate of 56 cases per 1,000 person-years in areas of high disease transmission. In areas where no symptomatic cases were detected, the incidence of asymptomatic or mild infection was 8 cases per 1,000 person-years. Dengue-2 virus was the predominant serotype identified, but all four serotypes were detected among the cohort. Four cases of DHF and one case of dengue shock syndrome (DSS) were identified. Three of the four DHF cases were due to DEN-3 virus. The one DSS case occurred in the setting of a prior DEN-2 virus infection, followed by a secondary infection with DEN-1 virus. To our knowledge, this is the first report of a longitudinal cohort study of naturally acquired DF and DHF in adults.
TL;DR: Infection and growth experiments showed that dengue serotype 2 viruses causing d Dengue hemorrhagic fever epidemics (Southeast Asian genotype) can outcompete viruses that causedengue fever only (American genotype).
Abstract: Dengue is the most common mosquito-borne viral disease in humans. The spread of both mosquito vectors and viruses has led to the resurgence of epidemic dengue fever (a self-limited flu-like syndrome) and the emergence of dengue hemorrhagic fever (severe dengue with bleeding abnormalities) in urban centers of the tropics. There are no animal or laboratory models of dengue disease; indirect evidence suggests that dengue viruses differ in virulence, including their pathogenicities for humans and epidemic potential. We developed two assay systems (using human dendritic cells and Aedes aegypti mosquitoes) for measuring differences in virus replication that correlate with the potential to cause hemorrhagic dengue and increased virus transmission. Infection and growth experiments showed that dengue serotype 2 viruses causing dengue hemorrhagic fever epidemics (Southeast Asian genotype) can outcompete viruses that cause dengue fever only (American genotype). This fact implies that Southeast Asian genotype viruses will continue to displace other viruses, causing more hemorrhagic dengue epidemics.
TL;DR: It is found that strict application of the WHO criteria fails to detect a significant number of patients with severe manifestations of dengue, especially in adults.
Abstract: The World Health Organization (WHO) scheme for classification of dengue severity was evaluated in a three-year study of 1,671 confirmed dengue cases in three Nicaraguan hospitals. The WHO classification of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) was compared with the presence of hemorrhagic manifestations, signs of vascular permeability, marked thrombocytopenia, and shock in 114 infants, 1,211 children, and 346 adults. We found that strict application of the WHO criteria fails to detect a significant number of patients with severe manifestations of dengue, especially in adults.
TL;DR: The situation is now so acute that it is not possible to wait for the perfect vaccine, and the careful and thorough evaluation of several of the current candidate vaccines may be the best approach to halting the spread of disease.
Abstract: In the second half of the twentieth century dengue spread throughout the tropics, threatening the health of a third of the world's population. Dengue viruses cause 50-100 million cases of acute febrile disease every year, including more than 500,000 reported cases of the severe forms of the disease--dengue haemorrhagic fever and dengue shock syndrome. Attempts to create conventional vaccines have been hampered by the lack of suitable experimental models, the need to provide protection against all four serotypes simultaneously and the possible involvement of virus-specific immune responses in severe disease. The current understanding of dengue pathogenesis is outlined in this review, with special emphasis on the role of the immune response. The suspected involvement of the immune system in increased disease severity and vascular damage has raised concerns about every vaccine design strategy proposed so far. Clearly more research is needed on understanding the correlates of protection and mechanisms of pathogenesis. There is, however, an urgent need to provide a solution to the escalating global public health problems caused by dengue infections. Better disease management, vector control and improved public health measures will help reduce the current disease burden, but a safe and effective vaccine is probably the only long-term solution. Although concerns have been raised about the possible safety and efficacy of both conventional and novel vaccine technologies, the situation is now so acute that it is not possible to wait for the perfect vaccine. Consequently the careful and thorough evaluation of several of the current candidate vaccines may be the best approach to halting the spread of disease.
TL;DR: The results indicate that dengue prevention, control, and research should be considered equally important as that of diseases currently given priority in southeast Asia.
Abstract: Dengue fever and dengue hemorrhagic fever constitute a substantial health burden on the population in Thailand. In this study, the impact of symptomatic dengue virus infection on the families of patients hospitalized at the Kamphaeng Phet Provincial Hospital with laboratory-confirmed dengue in 2001 was assessed, and the disability-adjusted life years (DALYs) lost for fatal and non-fatal cases of dengue were calculated using population level data for Thailand. When we accounted for the direct cost of hospitalization, indirect costs due to loss of productivity, and the average number of persons infected per family, we observed a financial loss of approximately US$61 per family, which is more than the average monthly income in Thailand. The DALYs were calculated using select results from a family level survey, and resulted in an estimated 427 DALYs/million population in 2001. This figure is of the same order of magnitude as the impact of several diseases currently given priority in southeast Asia, such as the tropical cluster (trypanosomiasis, Chagas disease, schistosomiasis, leishmaniasis, lymphatic filariasis, and onchocerciasis), malaria, meningitis, and hepatitis. These results indicate that dengue prevention, control, and research should be considered equally important as that of diseases currently given priority.
TL;DR: This work used ecological niche modeling via a genetic algorithm to produce time-specific predictive models of monthly distributions of Aedes aegypti in Mexico in 1995, indicating that predicting spatiotemporal dynamics of disease vector species is feasible and provides new potential for optimizing use of resources for disease prevention and remediation via automated forecasting of disease transmission risk.
Abstract: Numerous human diseases-malaria, dengue, yellow fever and leishmaniasis, to name a few-are transmitted by insect vectors with brief life cycles and biting activity that varies in both space and time. Although the general geographic distributions of these epidemiologically important species are known, the spatiotemporal variation in their emergence and activity remains poorly understood. We used ecological niche modeling via a genetic algorithm to produce time-specific predictive models of monthly distributions of Aedes aegypti in Mexico in 1995. Significant predictions of monthly mosquito activity and distributions indicate that predicting spatiotemporal dynamics of disease vector species is feasible; significant coincidence with human cases of dengue indicate that these dynamics probably translate directly into transmission of dengue virus to humans. This approach provides new potential for optimizing use of resources for disease prevention and remediation via automated forecasting of disease transmission risk.
TL;DR: Rain, temperature and relative humidity are highlighted as the major and important climatic factors, which could alone or collectively be responsible for an outbreak of dengue fever during the year 2003.
Abstract: This study was designed to find out a relationship of dengue infection with climatic factors such as rainfall, temperature and relative humidity during the dengue fever epidemic in the year 2003. Blood samples were collected from 1550 patients experiencing a febrile illness clinically consistent with dengue infection. Serological confirmation of Dengue Infection was done using Dengue Duo IgM and IgG Rapid Strip test (Pan Bio, Australia), which detected dengue-specific antibodies. Monthly data of total rainfall, temperature and relative humidity for the year 2003 was obtained from Meteorological Department of Delhi, New Delhi and retrospectively analyzed. Out of 1550 suspected cases, 893 cases (57.36%) were confirmed as serologically positive. The difference between numbers of serologically positive cases during different months was significant (p < 0.05). Larger proportions of serologically positive cases were observed among adults. Outbreak coincided mainly with the post monsoon period of subnormal rainfall. The difference between serologically positive cases as compared to serologically negative ones in post monsoon period was significantly higher (p < 0.001). The difference in the rainfall and temperature between three seasonal periods was significant (p < 0.05). This prospective study highlighted rain, temperature and relative humidity as the major and important climatic factors, which could alone or collectively be responsible for an outbreak. More studies in this regard could further reveal the correlation between the climatic changes and dengue outbreaks, which would help in making the strategies and plans to forecast any outbreak in future well in advance.
TL;DR: Empirical relationship of climatic factors rainfall, temperature and humidity with the DF/DHF incidences using multivariate regression analysis and a GIS based methodology is proposed in this paper to explore the influence of physio-environmental factors on dengue incidences.
Abstract: Background
Vector-borne diseases are the most dreaded worldwide health problems. Although many campaigns against it have been conducted, Dengue Fever (DF) and Dengue Haemorrhagic Fever (DHF) are still the major health problems of Thailand. The reported number of dengue incidences in 1998 for the Thailand was 129,954, of which Sukhothai province alone reported alarming number of 682. It was the second largest epidemic outbreak of dengue after 1987. Government arranges the remedial facilities as and when dengue is reported. But, the best way to control is to prevent it from happening. This will be possible only when knowledge about the relationship of DF/DHF with climatic and physio-environmental agents is discovered. This paper explores empirical relationship of climatic factors rainfall, temperature and humidity with the DF/DHF incidences using multivariate regression analysis. Also, a GIS based methodology is proposed in this paper to explore the influence of physio-environmental factors on dengue incidences. Remotely sensed data provided important data about physical environment and have been used for many vector borne diseases. Information Values (IV) method was utilised to derive influence of various factors in the quantitative terms. Researchers have not applied this type of analysis for dengue earlier. Sukhothai province was selected for the case study as it had high number of dengue cases in 1998 and also due to its diverse physical setting with variety of land use/land cover types.
TL;DR: The results highlight the importance of NS3 and cross-reactive T cells during acute secondary infection but suggest that the overall breadth and magnitude of the T-cell response is not significantly related to clinical disease grade.
Abstract: T-cell responses to dengue viruses may be important in both protective immunity and pathogenesis. This study of 48 Vietnamese adults with secondary dengue virus infections defined the breadth and magnitude of peripheral T-cell responses to 260 overlapping peptide antigens derived from a dengue virus serotype 2 (DV2) isolate. Forty-seven different peptides evoked significant gamma interferon enzyme-linked immunospot (ELISPOT) assay responses in 39 patients; of these, 34 peptides contained potentially novel T-cell epitopes. NS3 and particularly NS3200-324 were important T-cell targets. The breadth and magnitude of ELISPOT responses to DV2 peptides were independent of the infecting dengue virus serotype, suggesting that cross-reactive T cells dominate the acute response during secondary infection. Acute ELISPOT responses were weakly correlated with the extent of hemoconcentration in individual patients but not with the nadir of thrombocytopenia or overall clinical disease grade. NS3556-564 and Env414-422 were identified as novel HLA-A*24 and B*07-restricted CD8+ T-cell epitopes, respectively. Acute T-cell responses to natural variants of Env414-422 and NS3556-564 were largely cross-reactive and peaked during disease convalescence. The results highlight the importance of NS3 and cross-reactive T cells during acute secondary infection but suggest that the overall breadth and magnitude of the T-cell response is not significantly related to clinical disease grade.
TL;DR: It is demonstrated that nonobese diabetic/severely compromised immunodeficient mice xenografted with human CD34+ cells develop clinical signs of DF as in humans (fever, rash, and thrombocytopenia) when infected in a manner mimicking mosquito transmission (dose and mode).
Abstract: The increased transmission and geographic spread of dengue fever (DF) and its more severe presentation, dengue hemorrhagic fever (DHF), make it the most important mosquito-borne viral disease of humans (50 to 100 million infections/year) (World Health Organization, Fact sheet 117, 2002). There are no vaccines or treatment for DF or DHF because there are no animal or other models of human disease; even higher primates do not show symptoms after infection (W. F. Scherer, P. K. Russell, L. Rosen, J. Casals, and R. W. Dickerman, Am. J. Trop. Med. Hyg. 27:590-599, 1978). We demonstrate that nonobese diabetic/severely compromised immunodeficient (NOD/SCID) mice xenografted with human CD34+ cells develop clinical signs of DF as in humans (fever, rash, and thrombocytopenia), when infected in a manner mimicking mosquito transmission (dose and mode). These results suggest this is a valuable model with which to study pathogenesis and test antidengue products.
TL;DR: A review of the present Ae.
Abstract: An Asiatic mosquito species, Aedes albopictus, began to spread worldwide in the 1970s thanks to marine transport of tires and other goods, leading to colonization of many areas of the world. This species is a vector of major human diseases such as Dengue, Yellow Fever and the West Nile virus. In Europe, it was established in Albania and Italy and has been detected in other countries such as France; no records exist for Spain as yet. Colonization by Aedes albopictus is a major public health concern considering that the West Nile virus and several other viruses are known to circulate sporadically in the Mediterranean. Additionally, the parent species Aedes aegypti was the vector causing severe outbreaks of Dengue and Yellow Fever two centuries ago. Although Ae. aegypti was also introduced, it was eradicated from Spain. Both mosquitoes shared habitat types, diseases transmitted and many bionomic data. This article contains a review of the present Ae. albopictus distribution range worldwide and discusses the likelihood of an establishment in Spain in view of climatological and geographical data.
TL;DR: The results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.
Abstract: Antibody-dependent enhancement (ADE), a phenomenon in which viral replication is increased rather than decreased by immune sera, has been observed in vitro for a large number of viruses of public health importance, including flaviviruses, coronaviruses, and retroviruses. The most striking in vivo example of ADE in humans is dengue hemorrhagic fever, a disease in which ADE is thought to increase the severity of clinical manifestations of dengue virus infection by increasing virus replication. We examine the epidemiological impact of ADE on the prevalence and persistence of viral serotypes. Using a dynamical system model of n cocirculating dengue serotypes, we find that ADE may provide a competitive advantage to those serotypes that undergo enhancement compared with those that do not, and that this advantage increases with increasing numbers of cocirculating serotypes. Paradoxically, there are limits to the selective advantage provided by increasing levels of ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.
Journal Article•
TL;DR: Future challenges in the study of dengue and DHF include the application of modern techniques, such as nucleic acid chips, protein chips and new biomarkers to avoid cross-reactivity among different serotypes of d Dengue viruses and other flaviviruses, plus development of internationally standardized guidelines to improve quality assurance of these advanced laboratory tests.
Abstract: Since no protective vaccine or specific treatments are available for dengue fever/dengue hemorrhagic fever (DHF), accurate diagnosis is critical for the early initiation of specific preventive health measures to curtail epidemic spread and reduce economic losses. Commonly used diagnosis methods for confirming dengue infection involve virus isolation, detection of virus antigen or RNA in plasma or serum or tissues, and the presence of dengue virus-specific antibodies in serum and other body fluids. Recently, several techniques have been developed for rapid laboratory diagnosis of dengue virus, including centrifugation amplification to enhance virus isolation rate, the flow cytometry method for early detection of cultured virus, detecting viral nucleic acid e.g., by nested reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative RT-PCR, nucleic acid sequence-based amplification, and real-time PCR, detecting free viral non-structure antigens, anti-dengue virus immunoglobulin M (IgM) or IgG antibodies by enzyme-linked immunosorbent assay, and differentiation of primary versus secondary dengue virus infection. Newly established methods must be standardized to maintain high quality laboratory performance. Laboratory diagnostics must be tailored to a specific laboratory environment, the objectives of clinical needs and the availability of clinical specimens. Speed and accuracy of diagnosis must be balanced against test cost and availability. Future challenges in the study of dengue and DHF include the application of modern techniques, such as nucleic acid chips, protein chips and new biomarkers to avoid cross-reactivity among different serotypes of dengue viruses and other flaviviruses, plus development of internationally standardized guidelines to improve quality assurance of these advanced laboratory tests.
TL;DR: Using STAT1−/− mice bearing two different mutant stat1 alleles in the 129/Sv/Ev background, it is demonstrated that IFNR-dependent control of primary DEN infection involves both STAT1-dependent andSTAT1-independent mechanisms.
Abstract: Dengue virus (DEN), a flavivirus, causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, the most common mosquito-borne viral illnesses in humans worldwide. In this study, using STAT1(-/-) mice bearing two different mutant stat1 alleles in the 129/Sv/Ev background, we demonstrate that IFNR-dependent control of primary DEN infection involves both STAT1-dependent and STAT1-independent mechanisms. The STAT1 pathway is necessary for clearing the initial viral load, whereas the STAT1-independent pathway controls later viral burden and prevents DEN disease in mice. The STAT1-independent responses in mice with primary DEN infection included the early activation of B and NK cells as well as the up-regulation of MHC class I molecules on macrophages and dendritic cells. Infection of bone marrow-derived dendritic cell cultures with either DEN or Sindbis virus, another positive-strand RNA virus, confirmed the early vs late natures of the STAT1-dependent and STAT1-independent pathways. Collectively, these data begin to define the nature of the STAT1-dependent vs the STAT1-independent pathway in vivo.
TL;DR: Dengue virus type 4 in the Americas has a clear geographic structure that maintains viral diversity between outbreaks, indicative of a more rapid rate of exponential population growth in DENV-4 or a higher rate of geographic dispersal, allowing this virus to move more effectively among localities.
Abstract: Dengue virus type 4 (DENV-4) was first reported in the Americas in 1981, where it caused epidemics of dengue fever throughout the region. In the same year, the region's first epidemic of dengue hemorrhagic fever was reported, caused by an Asian strain of dengue virus type 2 (DENV-2) that was distinct from the American subtype circulating previously. Despite the importance of these epidemics, little is known about the rates or determinants of viral spread among island and mainland populations or their directions of movement. We employed a Bayesian coalescent approach to investigate the transmission histories of DENV-2 and DENV-4 since their introduction in 1981 and a parsimony method to assess patterns of strain migration. For both viruses there was an initial invasion phase characterized by an exponential increase in the number of DENV lineages, after which levels of genetic diversity remained constant despite reported fluctuations in DENV-2 and DENV-4 activity. Strikingly, viral lineage numbers increased far more rapidly for DENV-4 than DENV-2, indicative of a more rapid rate of exponential population growth in DENV-4 or a higher rate of geographic dispersal, allowing this virus to move more effectively among localities. We propose that these contrasting dynamics may reflect underlying differences in patterns of host immunity. Despite continued gene flow along particular transmission routes, the overall extent of viral traffic was less than expected under panmixis. Hence, DENV in the Americas has a clear geographic structure that maintains viral diversity between outbreaks.
TL;DR: The ability of infecting DV to counter the innate antiviral immunity might account for differences in virulence observed between viral strains.
TL;DR: The authors collected acute-phase serum samples from febrile patients at 2 major hospitals in Dhaka, Bangladesh, during an outbreak of dengue fever in 2001 and found that the case-fatality rate among leptospirosis patients (5%) was higher than among d Dengue fever patients (1.2%).
Abstract: We collected acute-phase serum samples from febrile patients at 2 major hospitals in Dhaka, Bangladesh, during an outbreak of dengue fever in 2001. A total of 18% of dengue-negative patients tested positive for leptospirosis. The case-fatality rate among leptospirosis patients (5%) was higher than among dengue fever patients (1.2%).
Journal Article•
TL;DR: The Weil-Felix test was introduced for the investigation of cases of FUO in Himachal Pradesh, India, and the results until April 2004 revealed the presence of other rickettsial infections prevalent in the region.
Abstract: In Indira Gandhi Medical College, Himachal Pradesh, India, during autumn of 2003 (September-November), more than 100 cases of fever of unknown origin (FUO) were reported with 15 ensuing deaths. In addition to all routine investigations and cultures, the Weil-Felix test was incorporated for the investigation of these cases. Antigen was procured from the Central Research Institute, Kasauli. Forty-six percent (45/96) of the cases demonstrated a > or =1:80 titer of agglutinins against OXK antigen. A team from the National Institute of Communicable Diseases, New Delhi, confirmed the antibodies for scrub typhus in some of the serum samples tested for leptospirosis, dengue fever, and rickettsial infections. Twelve blood samples positive for OXK antigen were sent to the Defense Research Development Establishment, Gwalior, for polymerase chain reaction studies, but none of the samples were positive, as all of the patients were already on broad-spectrum antibiotics and had reported to our hospital after 7-10 days of fever. At our institute, the Weil-Felix test has now been rountinely introduced for the investigation of cases of FUO, and the results until April 2004 (150 cases) revealed the presence of other rickettsial infections prevalent in the region. To evaluate the epidemiology and magnitude of the problem, further prospective studies are required.