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PubMed2006

NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease.

During the innate immune response against infections, Natural Killer (NK) cells are as important effector cells as are Cytotoxic T lymphocytes (CTL) generated after antigenic stimulation in the adaptative response. NK cells increase in numbers, after viral infection or vaccination. We investigated the NK cell and CD8 T lymphocyte status in 55 dengue infected patients. The NK (CD56+CD3-) and CD56+ T cell (CD56+CD3+) rates rise during the acute phase of disease. The majority of NK cells from dengue patients display early markers for activation (CD69, HLA-DR, and CD38) and cell adhesion molecules (CD44, CD11a) during the acute phase of disease. The intracellular cytotoxic granule, TIA-1, is also up-regulated early in NK cells. Most of these markers appear also on CD8+ T lymphocytes but during the late acute phase. Circulating IL-15 is elevated in a significant number of patients during early acute infection and its values were statistically correlated with NK frequencies and cytotoxic markers on NKs. We have therefore shown that dengue virus infection is very likely stimulating a cytotoxic response that may be efficient in controlling the virus in synergism with CD8+ T lymphocytes. Interestingly, the heightened CD56+CD3-, CD56+CD3+, CD56+TIA-1+ and CD56+CD11a+ cell rates are associated with mild dengue clinical manifestations and might indicate a good prognosis of the disease.

Adolescent↗
PubMed1992

Dengue encephalopathy.

Dengue encephalopathy or dengue hemorrhagic fever (DHF) with CNS involvement used to be considered a relatively rare condition; but the number of cases reported in human studies has been increasing every year. Diagnosis of dengue encephalopathy is based on clinically diagnosed DHF according to the W.H.O. criteria (1980), with CNS manifestations consisting of abrupt onset of hyperpyrexia, non-transient alteration of consciousness, headache, vomiting--with or without seizures--and normal CSF. Many factors may be considered to be directly or indirectly associated with CNS signs and symptoms in DHF, the main pathology being leakage of plasma into serous spaces and abnormal hemostasis, leading to hypovolemic shock and hemorrhage in many organs of the body. Acute liver failure is considered to be one of the main factors causing brain pathology. One hundred fifty-two cases of dengue encephalopathy admitted during 3 periods at the Cipto Mangunkusumo Hospital in Jakarta were studied retrospectively. The overall incidence was 152 out of 2,441 DHF cases, or 6.2%. The most pronounced symptoms were hyperpyrexia, alteration of consciousness and convulsions. Laboratory examination showed an unusually high increase of serum transaminases, hyponatremia, and hypoxia. Neurologic abnormalities detected were hemiparesis and tetraparesis of the extremities, and second nerve atrophy; such abnormalities were found in 10 out of the 152 cases, or 6.5%.

Age Factors↗
PubMed2001

Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever.

Interleukin (IL)-13 is produced by T helper 2 (Th2)-type cells and inhibits the production of proinflammatory cytokines by activated monocytes, while IL-18 is a pleiotropic cytokine that induces interferon-gamma and plays an important role in the development of Th1-type cells. Role of the shift from a Th1-type response to Th2-type has been suggested in the pathogenesis of dengue hemorrhagic fever (DHF). This study was undertaken to investigate the possible protective/pathogenic role of IL-13 and IL-18 in patients with DHF. Sera were collected from a total of 84 patients with various grades of dengue illness and 21 normal healthy controls and tested for IL-13 and IL-18 levels using commercial enzyme-linked immunosorbent assay kits. The results showed that very low levels of IL-13 (4+/-3 pg ml(-1)) and IL-18 (15+/-4 pg ml(-1)) were detected in the sera of healthy controls. In dengue patients, the levels of IL-13 and IL-18 were the highest in the patients with DHF grade IV (205+/-103 pg ml(-1) and 366+/-155 pg ml(-1), respectively) and the lowest in patients with dengue fever (22+/-12 pg ml(-1) and 76+/-50 pg ml(-1), respectively). Both the cytokines appeared (IL-13=20+/-11 pg ml(-1) and IL-18=70+/-45 pg ml(-1)) during the first 4 days of illness and reached peak levels (IL-13=204+/-96 pg ml(-1) and IL-18=360+/-148 pg ml(-1)) by day 9 onwards. The presence of high levels of IL-13 and IL-18 during severe illness and late phases of the disease suggests that both of these cytokines may contribute to the shift from a Th1- to Th2-type response and thus to the pathogenesis of DHF.

Humans↗
PubMed2006

Comparison by flow cytometry of immune changes induced in human monocyte-derived dendritic cells upon infection with dengue 2 live-attenuated vaccine or 16681 parental strain.

Dengue is an important threat for world-wide public health. Different vaccines are under development, which are currently assessed using a battery of in vitro and in vivo assays before moving on to humans. It is also important to assess vaccine characteristics on human primary cells; among them, dendritic cells, the most efficient antigen-presenting cells, are the first targets of dengue virus infection. In this study, we used flow cytometry to compare the consequences of such an infection by dengue serotype 2 live-attenuated vaccine (LAV2) or its parental strain DEN2 16681 (DEN2). Optimal conditions of infection have first been defined by a mathematical approach, and flow cytometry allowed studying modifications induced in both infected and noninfected dendritic cell populations after surface and intracellular labeling. Both DEN2 and LAV2 increased the expression of the phenotypic markers CD80, CD86, CD40, CD1a, HLA ABC and CD83, demonstrating cellular activation. Stimulated dendritic cells produced tumor necrosis factor-alpha in particular, and, to a lower extent, interleukin 6. Of importance, whereas DEN2 induced cytokine production both in the infected and noninfected populations, LAV2-induced cytokine production was restricted to the infected population. This limited activation triggered by LAV2 would be in agreement with its attenuation. In conclusion, these in vitro experiments using primary human dendritic cells may participate, in combination with other assays, to the evaluation of the immunogenicity and safety of dengue vaccine candidates.

Antigens, Surface↗
PubMed1995

A serotype-specific epitope of dengue virus 1 identified by phage displayed random peptide library.

From a panel of monoclonal antibodies of dengue viruses, a serotype-specific epitope of dengue virus 1 was screened from a random peptide library displayed on phage. The epitope was the determinant reactive with monoclonal antibody 15F3-1 that was specific to dengue 1. The screening was monitored by a dot blotting procedure, and after three rounds of screening a consensus motif, HRYSWK, was found. This sequence matches the sequence HKYSWK, corresponding to the amino acid residues 885-890 of polyprotein or residues 111-116 of the non-structural protein 1 of dengue virus serotype 1. The linear epitope was confirmed by testing the antigenicity of chemically synthesized 8-branched peptide.

Amino Acid Sequence↗
PubMed1978

Replication of dengue and junin viruses in cultured rabbit and human endothelial cells.

The flavivirus dengue and the arenavirus Junin are both associated with a hemorrhagic shock syndrome in man. We have demonstrated the replication of these viruses in vitro in both rabbit and human endothelial cells by viral titers and immunofluorescent antibody studies. Rabbit endothelium established in continuous culture was derived from vena cava, while human cells in primary culture were derived from umbilical veins. In rabbit endothelium, dengue-2 virus passaged through monkey kidney monolayer cells (LLC-MK2) or human lymphoblastoid cells (raji) produced significantly more virus than the seed obtained from suckling mouse brain (MB). Inoculation of actively dividing, subconfluent human endothelial cells with the LLC-MK2 degue virus produced higher viral titers than inoculation of confluent cells. The appearance of Junin virus was delayed beyond that of dengue virus in rabbit endothelial cells although equivalent titers of virus were produced. In human cells, Junin virus was less productive than dengue virus and produced characteristic cycles of virus release. This is the first direct evidence for replication of human hemorrhagic fever viruses in endothelial cells.

Animals↗
PubMed1982

Infection enhancement of dengue type 2 virus in the U-937 human monocyte cell line by antibodies to flavivirus cross-reactive determinants.

Dengue type 2 virus replication was detected in the U-937 human monocyte cell line when the virus inoculum and the culture medium contained flavivirus antibodies diluted beyond their neutralizing titers. This was in marked contrast to yellow fever virus, which replicated very well in the absence of antibodies; however, 10-fold-higher yields of yellow fever virus could be obtained in the presence of flavivirus antibodies. These infection-enhancing antibodies were obtained from either a dengue type 2 human antiserum or reference hyperimmune obtained from either a dengue type 2 human antiserum or reference hyperimmune mouse ascitic fluid. The infection enhancement phenomenon, previously shown to be due to infection of Fc receptor-bearing cells with virus-antibody complexes, was completely blocked by preincubation of the cells with aggregated gamma globulin. The blocking results suggested an Fc receptor-mediated infection of the U-937 cells as well. A panel of monoclonal antibodies, previously characterized as either virus type specific or flavivirus cross-reactive and with mouse immunoglobulin subclasses G1 and G2a in both categories, were tested for their infection enhancement characteristics. A type-specific neutralizing monoclonal antibody preparation that was diluted beyond its neutralization titer did not cause infection enhancement, nor did low-level neutralizing monoclonal antibodies that were dengue serotype specific by the hemagglutination inhibition test. Only flavivirus cross-reactive monoclonal antibodies caused infection enhancement, irrespective of whether the immunoglobulins were G1 or G2a. These cross-reactive flavivirus determinants may reside at the tips of the glycoprotein projections on the virus particles, enabling the Fc ends of the cross-reactive antibodies attached to these determinants to interact with Fc receptors on susceptible cells.

Antibodies, Monoclonal↗
PubMed1987

Expression of dengue virus structural proteins and nonstructural protein NS1 by a recombinant vaccinia virus.

A recombinant vaccinia virus containing cloned DNA sequences coding for the three structural proteins and nonstructural proteins NS1 and NS2a of dengue type 4 virus was constructed. Infection of CV-1 cells with this recombinant virus produced dengue virus structural proteins as well as the nonstructural protein NS1. These proteins were precipitated by specific antisera and exhibited the same molecular size and glycosylation patterns as authentic dengue virus proteins. Infection of cotton rats with the recombinant virus induced NS1 antibodies in 1 of 11 animals. However, an immune response to the PreM and E glycoproteins was not detected. A reduced level of gene expression was probably the reason for the limited serologic response to these dengue virus antigens.

Animals↗
PubMed1989

In vitro processing of dengue virus structural proteins: cleavage of the pre-membrane protein.

Processing of dengue virus structural proteins was assessed in vitro. RNA transcripts for cell-free translation were prepared from cloned DNA (dengue virus type 4, strain 814669 genome) encoding capsid, pre-membrane (prM), and the first 23 amino acids of envelope (E). Processing of a 33-kilodalton precursor polypeptide encoded by wild-type RNA transcripts occurred only in the presence of added microsomal membranes. Under these conditions, cleavage at the capsid-prM and prM-E sites and glycosylation of prM occurred in association with translocation. Amino acid sequence analysis confirmed that translation initiated at the predicted N terminus of the capsid and that capsid-prM cleavage occurred at the predicted site for the action of signal peptidase following a candidate signal sequence (hydrophobic residues 100 to 113) in the dengue virus precursor. Mutations were introduced into the dengue virus DNA template by site-directed mutagenesis, altering nucleotide sequences encoding the capsid and the candidate signal for prM. The phenotypes of the mutants were deduced by analysis of the products of cell-free translation of the respective RNA transcripts. The resulting observations confirmed that cleavage at the capsid-prM and prM-E sites is effected entirely by signal peptidase and that the candidate signal is required for translocation.

Amino Acid Sequence↗
PubMed1995

Construction of intertypic chimeric dengue viruses exhibiting type 3 antigenicity and neurovirulence for mice.

There are four dengue virus serotypes (DEN1 to -4), each of which causes major epidemics in tropical or subtropical areas. The current strategy for dengue virus immunization favors the use of a tetravalent vaccine preparation. We have previously employed full-length DEN4 cDNA to construct a viable intertypic dengue virus type 1 or type 2 chimera that contained the C-PreM-E or only the PreM-E genes of DEN1 or DEN2 substituting for the corresponding genes of DEN4. This success implied that it might be possible to create mutants of all four dengue virus serotypes for evaluation as candidate vaccines. In this study, we constructed DEN3-DEN4 chimeras that contained DEN3 C-PreM-E genes and expressed DEN3 antigenic specificity. Unlike our previous successes in cloning DEN1 or DEN2 chimeric cDNA, we were not able to clone the DEN3 C-PreM-E genes directly in the 5' intermediate vector or in the full-length chimeric DEN3-DEN4 plasmid in Escherichia coli. Nevertheless, a full-length DNA template of DEN3-DEN4 that could be used for transcription of infections RNAs was prepared by in vitro ligation. Progeny virus recovered from RNA-transfected C6/36 mosquito cells exhibited DEN3 antigenic specificity as determined by a reaction with monoclonal antibodies. Gel electrophoresis of virus-infected cell lysates yielded the predicted viral protein pattern, i.e., DEN3 C, PreM, and E and DEN4 nonstructural proteins. Two amino acid substitutions, Thr-435-->Leu and Glu-406-->Lys, which are analogous to mutations that, respectively, confer mouse neurovirulence on DEN4 and DEN2, were introduced into DEN3 E. A mutant chimera containing the Thr-435-->Leu substitution, which ablates the potential glycosylation site sequence, produced an E protein identical in size to that of wild-type DEN3 E, indicating that the glycosylation site is normally not used. Intracerebral inoculation of suckling mice revealed that the mutant chimera containing the Glu-406-->Lys substitution was neurovirulent, whereas its wild-type counterpart or parent DEN3 was not.

Animals↗
PubMed1998

Genetic determinants responsible for acquisition of dengue type 2 virus mouse neurovirulence.

Studies conducted some 50 years ago showed that serial intracerebral passage of dengue viruses in mice selected for neurovirulent mutants that also exhibited significant attenuation for humans. We investigated the genetic basis of mouse neurovirulence of dengue virus because it might be directly or indirectly associated with attenuation for humans. Analysis of the sequence in the C-PreM-E-NS1 region of the parental dengue type 2 virus (DEN2) New Guinea C (NGC) strain and its mouse-adapted, neurovirulent mutant revealed that 10 nucleotide changes occurred during serial passage in mice. Seven of these changes resulted in amino acid substitutions, i.e., Leu55-Phe and Arg57-Lys in PreM, Glu71-Asp, Glu126-Lys, Phe402-Ile, and Thr454-Ile in E, and Arg105-Gln in NS1. The sequence of C was fully conserved between the parental and mutant DEN2. We constructed intertypic chimeric dengue viruses that contained the PreM-E genes or only the NS1 gene of neurovirulent DEN2 NGC substituting for the corresponding genes of DEN4. The DEN2 (PreM-E)/DEN4 chimera was neurovirulent for mice, whereas DEN2 (NS1)/DEN4 was not. The mutations present in the neurovirulent DEN2 PreM-E genes were then substituted singly or in combination into the sequence of the nonneurovirulent, parental DEN2. Intracerebral titration of the various mutant chimeras so produced identified two amino acid changes, namely, Glu71-Asp and Glu126-Lys, in DEN2 E as being responsible for mouse neurovirulence. The conservative amino acid change of Gu71-Asp probably had a minor effect, if any. The Glu126-Lys substitution in DEN2 E, representing a change from a negatively charged amino acid to a positively charged amino acid, most likely plays an important role in conferring mouse neurovirulence.

Animals↗
PubMed2000

Release of vasoactive cytokines by antibody-enhanced dengue virus infection of a human mast cell/basophil line.

We report here the first demonstration of dengue virus infection and vasoactive cytokine response of a cell of the mast cell/basophil lineage. Infection of KU812 cells was dependent on dengue-specific antibody and gave rise to infectious virions. This antibody-enhanced dengue virus infection triggered a four- to fivefold increase in the release of interleukin-1beta (IL-1beta) and a modest increase for IL-6 but not for an alternate cytokine, granulocyte-macrophage colony-stimulating factor. The results suggest a potential role for mast cells/basophils in the pathogenesis of dengue virus-induced disease.

Animals↗
PubMed2005

Long-range RNA-RNA interactions circularize the dengue virus genome.

Secondary and tertiary RNA structures present in viral RNA genomes play essential regulatory roles during translation, RNA replication, and assembly of new viral particles. In the case of flaviviruses, RNA-RNA interactions between the 5' and 3' ends of the genome have been proposed to be required for RNA replication. We found that two RNA elements present at the ends of the dengue virus genome interact in vitro with high affinity. Visualization of individual molecules by atomic force microscopy revealed that physical interaction between these RNA elements results in cyclization of the viral RNA. Using RNA binding assays, we found that the putative cyclization sequences, known as 5' and 3' CS, present in all mosquito-borne flaviviruses, were necessary but not sufficient for RNA-RNA interaction. Additional sequences present at the 5' and 3' untranslated regions of the viral RNA were also required for RNA-RNA complex formation. We named these sequences 5' and 3' UAR (upstream AUG region). In order to investigate the functional role of 5'-3' UAR complementarity, these sequences were mutated either separately, to destroy base pairing, or simultaneously, to restore complementarity in the context of full-length dengue virus RNA. Nonviable viruses were recovered after transfection of dengue virus RNA carrying mutations either at the 5' or 3' UAR, while the RNA containing the compensatory mutations was able to replicate. Since sequence complementarity between the ends of the genome is required for dengue virus viability, we propose that cyclization of the RNA is a required conformation for viral replication.

Animals↗
PubMed2004

Internalization and propagation of the dengue virus in human hepatoma (HepG2) cells.

OBJECTIVES: This study sought to undertake a comparative analysis of the internalization and propagation of all four dengue serotypes in a single cell line of human liver origin, HepG2. METHODS: Virus production after infection was determined by the plaque assay technique. Internalization profiles were determined by incubating virus and cells on ice and then raising the temperature for various times. The contribution of extracellular matrix components to internalization was determined by pretreatment of cells with either trypsin or heparinase III. RESULTS: HepG2 cells were able to support the propagation of all four serotypes with mature viruses being produced by 12 h for dengue serotype 4 and by 17-18 h for the remaining serotypes. Virus internalization showed a plateau for serotypes 1, 2 and 4 entry while serotype 3 showed a constant increase in internalization for up to 5 h. Pretreatment of HepG2 cells with heparinase III or trypsin both resulted in a reduction in viral production, with the smallest effect being noted for dengue serotype 3. CONCLUSION: These results suggest that the interaction between the dengue virus and liver cells is a complex one that requires both protein and nonprotein elements, and has a significant serotype/strain element.

Cell Line, Tumor↗
PubMed2004

Bleeding and other presentations in Thai patients with dengue infection.

Dengue infection is a major public health problem, affecting the general population in Southeast Asia. Hematologic aberrations in dengue infection include atypical lymphocytosis, coagulopathy, and predominant thrombocytopenia. Bleeding and other presentations in 30 Thai patients with dengue infection during an endemic season (2003) are presented. A review of the clinical presentation of these patients was performed. All had fever as a chief complaint. The three most common complaints were fever (100%), vomiting (90%), and cough (90%), respectively. Concerning bleeding, only eight cases (26.6%) had signs of bleeding. Those manifestations included petechiae (seven cases, 23.3%) and melena (one case, 3.3%). Skin bleeding (petechiae) due to thrombocytopenia is the most common bleeding manifestation in dengue infection. However, physicians should not overlook bleeding from other less common sites such as the gastrointestinal tract and genitourinary tract.

Dengue↗
PubMed2006

Dengue virus infection: a major cause of acute hepatic failure in Thai children.

BACKGROUND: Acute hepatic failure (AHF) can be caused by a variety of viruses, drugs, toxins and metabolic disorders. AIMS: A prospective study was conducted to determine the aetiology and outcome of AHF in Thai children aged 1-15 years. METHODS: All serum samples were tested for anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HCV, anti-HEV IgM and anti-dengue IgG and IgM. Further individual investigations were done according to the clinical impression. RESULTS: Forty subjects were enrolled from 14 centres during February 2000 to December 2001. Five cases were excluded owing to a lack of evidence of encephalopathy. The causes of AHF were dengue infection in 12 (34.3%), Wilson disease in 2 (5.7%), T-cell lymphoma in 2 (5.7%), ischaemic hepatitis in two (5.7%), haemophagocytic syndrome in one (2.8%), CMV in 2 (5.7%), Reye syndrome in one (2.8%) and unknown in 13 (37.1%) patients. The fatality rate was 68.6%. Eight of 24 (33.3%) deaths were caused by dengue infection. CONCLUSIONS: Improvements in sanitation and socio-economic status as well as the implementation of hepatitis B vaccine in the Extended Programme on Immunization (EPI) are likely to be the reasons for the observed absence of AHF caused by hepatitis A and B. The study showed that dengue infection, on the other hand, was a major cause of AHF in Thailand.

Acute Disease↗
PubMed1991

[Dengue epidemic in Ribeirão Preto, SP, Brazil: a preliminary note].

A preliminary note on an outbreak of dengue which occurred in the city of Ribeirão Preto, State of S. Paulo, Brazil, from November 1990 to March 1991, is given. One case of Level II Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS) and two deaths associated with dengue related shock are described. Clinicians and epidemiologists are alerted to the possibility of sporadic DHF/DSS cases during outbreaks of classical dengue in formerly free areas.

Brazil↗
PubMed2005

[Identification of places with potential transmission of dengue fever in Porto Alegre using Geographical Information Systems].

The social-environmental conditions that promote the continuity of Aedes aegypti in urban areas and its capacity for dengue transmission have yet to be determined. The aim of this work was to locate dengue cases and vector presence, then to identify social-environmental factors that characterize these sites, through Geographical Information Systems (GIS), with a view to developing a dengue fever prevention model. The vector was mainly located in south and east areas of the city, with a broad dispersion, while most of the cases were located in the central region of the city. The sectors with cases present characteristics of high income. Otherwise, sectors with vector present a predominance of houses and good sanitation infrastructure. The difference between cases and vector spatial patterns ensured for 2002 an absence of dengue transmission in the city.

Aedes↗