Recent shift in age pattern of dengue hemorrhagic fever, Brazil.
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ABSTRACT:
SUBMITTER: Teixeira MG
PROVIDER: S-EPMC2609867 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dengue serotype 3 viruses were isolated from patients in Brazil from 2002 through 2004. On the basis of phylogenetic analyses, these isolates were assigned genotype 1. This genotype had never been reported in South America before. Its appearance indicates a major risk factor for dengue epidemics and severe disease.
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Project description:BackgroundGenetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations.MethodsWe conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls.FindingsThe risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other.InterpretationThere is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries.
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Project description:The simian hemorrhagic fever virus (SHFV) genome differs from those of other members of the family Arteriviridae in encoding three papain-like one proteases (PLP1α, PLP1β and PLP1γ) at the 5' end and two adjacent sets of four minor structural proteins at the 3' end. The catalytic Cys and His residues and cleavage sites for each of the SHFV PLP1s were predicted and their functionality was tested in in vitro transcription/translation reactions done with wildtype or mutant polyprotein constructs. Mass spectrometry analyses of selected autoproteolytic products confirmed cleavage site locations. The catalytic Cys of PLP1α is unusual in being adjacent to an Ala instead of a Typ. PLP1γ cleaves at both downstream and upstream sites. Intermediate precursor and alternative cleavage products were detected in the in vitro transcription/translation reactions but only the three mature nsp1 proteins were detected in SHFV-infected MA104 cell lysates with SHFV nsp1 protein-specific antibodies. The duplicated sets of SHFV minor structural proteins were predicted to be functionally redundant. A stable, full-length, infectious SHFV-LVR cDNA clone was constructed and a set of mutant infectious clones was generated each with the start codon of one of the minor structural proteins mutated. All eight of the minor structural proteins were found to be required for production of infectious extracellular virus. SHFV causes a fatal hemorrhagic fever in macaques but asymptomatic, persistent infections in natural hosts such as baboons. SHFV infections were compared in macrophages and myeloid dendritic cells from baboons and macaques. Virus yields were higher from macaque cells than from baboon cells. Macrophage cultures from the two types of animals differed dramatically in the percentage of cells infected. In contrast, similar percentages of myeloid dendritic cells were infected but virus replication was efficient in the macaque cells but inefficient in the baboon cells. SHFV infection induced the production of pro-inflammatory cytokines, including IL-1β, IL-6, IL-12/23(p40), TNF-α and MIP-1α, in macaque cells but not baboon cells.
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Project description:Dengue infection is the most prevalent arthropod-borne viral disease in subtropical and tropical regions, whose primary vector is Aedes aegypti mosquitoes. The mechanisms of dengue virus (DENV) pathogenesis are little understood because we have no good disease models. Only humans develop symptoms (dengue fever, DF, or dengue hemorrhagic fever, DHF) and research has been limited to studies involving patients. Samples from serum, brain, cerebellum, heart, lungs, liver, and kidneys from a 13-year-old male patient that died with hemorrhagic manifestations were sent for differential diagnosis at Adolfo Lutz, using both classical virological methods (RT-qPCR, virus isolation, ELISA, and hemagglutination inhibition test) and immunohistochemistry (IHQ). A DENV serotype 4 was detected by a DENV multiplex RT-qPCR, and the C6/36 cell supernatant was used for NGS using Minion. Lesions were described in the heart, liver, lung, and kidney with positive IHQ in endothelial cells of the brain, cerebellum, heart, and kidney, and also in hepatocytes and Kuppfer cells. A whole genome was obtained, revealing a DENV-4 genotype II, with no evidence of secondary dengue infection.
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Project description:Dengue fever (DF) and dengue hemorrhagic fever (DHF) are recurrent diseases that are widespread in the tropics. Here, we identified candidate genes associated with these diseases by performing integrated analyses of DF (GSE51808) and DHF (GSE18090) microarray datasets in the Gene Expression Omnibus (GEO). In all, we identified 7635 differentially expressed genes (DEGs) in DF and 8147 DEGs in DHF as compared to healthy controls (P < 0.05). In addition, we discovered 215 differentially expressed long non-coding RNAs (DElncRNAs) in DF and 225 DElncRNAs in DHF. There were 1256 common DEGs and eight common DElncRNAs in DHF vs DF, DHF vs normal control, and DF vs normal control groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that signal transduction (false discovery rate = 8.33E-10), 'toxoplasmosis', and 'protein processing in endoplasmic reticulum' were significantly enriched pathways for common DEGs. We conclude that the MAGED1,STAT1, and IL12A genes may play crucial roles in DF and DHF, and suggest that our findings may facilitate the identification of biomarkers and the development of new drug design strategies for DF and DHF treatment.
| S-EPMC6396354 | biostudies-literature
Project description:Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue.To explore the association of cytokine and socs levels with disease severity in dengue patients.Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR.Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF.Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.
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Project description:To identify genes associated with the clinical presentation of dengue, 50 cases of probable or possible dengue hemorrhagic fever (DHF), 236 dengue fever (DF), and 236 asymptomatic infections were genotyped for 593 single-nucleotide polymorphisms (SNPs) in 56 genes across the type 1 interferon (IFN) response pathway as well as other important candidate genes. By single locus analysis comparing DHF with DF, 11 of the 51 markers with P<0.05 were in the JAK1 gene. Five markers were significantly associated by false discovery rate criteria (q<0.20 when P<6 × 10(-4)). The JAK1 SNPs showed differential distribution by ethnicity and ancestry consistent with epidemiologic observations in the Americas. The association remained significant after controlling for ancestry and income. No association was observed with markers in the gene encoding CD209 (DC-SIGN). An association between DHF and JAK1 polymorphisms is in agreement with expression profiles showing generalized decreased type 1 IFN-stimulated gene expression in these patients.
| S-EPMC2950898 | biostudies-literature
Project description:BACKGROUND: Dengue virus (DENV) infection is the most common arthropod-borne viral disease in man and there are approximately 100 million infections annually. Despite the global burden of DENV infections many important questions regarding DENV pathogenesis remain unaddressed due to the lack of appropriate animal models of infection and disease. A major problem is the fact that no non-human species naturally develop disease similar to human dengue fever (DF) or dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Apart from other risk factors for severe dengue such as host genetics and secondary infection with a heterologous DENV, virus virulence is a risk factor that is not well characterized. RESULTS: Three clinical DENV-1 isolates from Cambodian patients experiencing the various forms of dengue disease (DF, DHF, and DSS) were inoculated in BALB/c mice at three different concentrations. The DENV-1 isolates had different organ and cell tropism and replication kinetics. The DENV-1 isolate from a DSS patient infected the largest number of mice and was primarily neurotropic. In contrast, the DENV-1 isolates from milder clinical dengue cases infected predominantly lungs and liver, and to a lesser extent brain. In addition, infection with the DENV isolate derived from a DSS patient persisted for more than two weeks in a majority of mice compared to the other DENV-1 isolates that peaked during the first week. CONCLUSIONS: These results confirm the in vitro findings of the same DENV-1 isolates, that showed that the isolate derived from a DSS patient can be distinguished based on phenotypic characteristics that differ from the isolates derived from a DF and DHF case 1. We observed in this study that the DSS virus isolate persist longer in vivo with extensive neuroinvasion in contrast to the other DENV-1 isolates originating in milder human cases. Genomic characterization of the three clinical isolates identified six amino acid substitutions unique for the DSS isolates that were located both in structural genes (M and E) and in non-structural genes (NS1, NS3, and NS5). The characterization of these clinically distinct DENV-1 isolates highlight that DENVs within the same genotype may have different in vivo phenotypes. HIGHLIGHTS: • Clinical DENV-1 isolates have different organ tropism in BALB/c mice.• The isolate from a DSS patient is primarily neurotropic compared to the other isolates.• The DENV-1 isolates have different in vivo replication kinetics.• The isolate from a DSS patient persists longer compared to the other isolates.• These phenotypic differences confirm our earlier in vitro findings with the same DENV-1 isolates. Thus, DENVs within the same serotype and genotype may differ enough to affect clinical conditions in vivo.
| S-EPMC3170302 | biostudies-literature
Project description:BackgroundDengue is the most prevalent arthropod-borne viral illness in humans with half of the world's population at risk. During early infancy, severe dengue can develop after a primary dengue virus infection. There has been a clinical observation that severe dengue during the first year of life is seen only in chubby infants.Methodology/principal findingsWe examined the associations between the development of severe dengue and adipose tissue accumulation patterns during the first year of life in a prospective observational clinical study of infants and dengue virus infections. We found that adipose tissue contains two potential targets for dengue virus infection and production- adipocytes and adipose tissue macrophages. During the first year of life, total body adiposity and visceral adipose tissue stores were at their highest levels in early infancy. Early infancy was also characterized by a relative decrease in alternatively activated (anti-inflammatory) macrophages, and a relative increase in circulating pro-inflammatory cytokines.Conclusions/significanceThe data has been used to propose a model where the adipose tissue accumulation pattern and pro-inflammatory environment during early infancy provide the conditions for the potential development of severe dengue in immune-susceptible infants.
| S-EPMC4670217 | biostudies-literature
Project description:BACKGROUND: Dengue is the most prevalent mosquito-borne virus, and potentially fatal dengue hemorrhagic fever (DHF) occurs mainly in secondary infections. It recently was hypothesized that, due to the presence of cross-immunity, the relationship between the incidence of DHF and transmission intensity may be negative at areas of intense transmission. We tested this hypothesis empirically, using vector abundance as a surrogate of transmission intensity. METHODOLOGY/PRINCIPAL FINDINGS: House Index (HI), which is defined as the percentage of households infested with vector larvae/pupae, was obtained from surveys conducted on one million houses in Thailand, between 2002 and 2004. First, the utility of HI as a surrogate of transmission intensity was confirmed because HI was correlated negatively with mean age of DHF in the population. Next, the relationship between DHF incidence and HI was investigated. DHF incidence increased only up to an HI of about 30, but declined thereafter. Reduction of HI from the currently maximal level to 30 would increase the incidence by more than 40%. Simulations, which implemented a recently proposed model for cross-immunity, generated results that resembled actual epidemiological data. It was predicted that cross-immunity generates a wide variation in incidence, thereby obscuring the relationship between incidence and transmission intensity. The relationship would become obvious only if data collected over a long duration (e.g., >10 years) was averaged. CONCLUSION: The negative relationship between DHF incidence and dengue transmission intensity implies that in regions of intense transmission, insufficient reduction of vector abundance may increase long-term DHF incidence. Further studies of a duration much longer than the present study, are warranted.
| S-EPMC2442222 | biostudies-other