BackgroundDengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking.Methodology/Principal FindingsIn this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the “early” group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0–1 and declined on day 3–4; the second “late” group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5–6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0–3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1.Conclusions/SignificanceOur study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1–3 may have applications in developing early molecular diagnostics for DHF.

Abstract. Dengue transmission in Venezuela has become perennial and a major public health problem. The increase in frequency and magnitude of recent epidemics prompted a comprehensive community-based cross-sectional study of 2,014 individuals in high-incidence neighborhoods of Maracay, Venezuela. We found a high seroprevalence (77.4%), with 10% of people experiencing recent infections. Multivariate logistic regression analysis showed that poverty-related socioeconomic factors (place and duration of residence, crowding, household size, and living in a shack) and factors/constraints related to intradomiciliary potential mosquito breeding sites (storing water and used tires) were linked with a greater risk of acquiring a dengue infection. Our results also suggest that transmission occurs mainly at home. The combination of increasingly crowded living conditions, growing population density, precarious homes, and water storage issues caused by enduring problems in public services in Maracay are the most likely factors that determine the permanent dengue transmission and the failure of vector control programs.

Abstract. Dengue virus infections are a major cause of morbidity in tropical countries. Early detection of dengue hemorrhagic fever (DHF) may help identify individuals that would benefit from intensive therapy. Predictive modeling was performed using 11 laboratory values of 51 individuals (38 DF and 13 DHF) obtained on initial presentation using logistic regression. We produced a robust model with an area under the curve of 0.9615 that retained IL-10 levels, platelets, and lymphocytes as the major predictive features. A classification and regression tree was developed on these features that were 86% accurate on cross-validation. The IL-10 levels and platelet counts were also identified as the most informative features associated with DHF using a Random Forest classifier. In the presence of polymerase chain reaction-proven acute dengue infections, we suggest a complete blood count and rapid measurement of IL-10 can assist in the triage of potential DHF cases for close follow-up or clinical intervention improving clinical outcome.

During the past 40 years, dengue haemorrhagic fever and dengue shock syndrome (DHF/DSS) have emerged in humans, with approximately 3 million cases reported and over 58 000 deaths. Dengue virus serotypes 1, 2 and 4 (DENV-1, -2 and -4) have been co-circulating in Venezuela for at least the past 10 years, causing minor or major outbreaks of dengue fever (DF) and DHF/DSS. The first recorded outbreak due to DENV-3 in Venezuela dates to 1964 and the virus then seems to have disappeared. However, DENV-3 re-appeared recently (in July, 2000) in Venezuela after 32 years of absence and produced a prolonged major outbreak, which, by the end of 2001, involved 83 180 cases of dengue, mostly DF (92 %). Previous phylogenetic studies revealed that the DENV-3 circulating during the 1960s Latin American outbreak was a genotype V virus. To gain a better understanding of the nature of the current epidemic, the complete sequence was determined of the envelope (E) gene of 15 Venezuelan DENV-3 viruses isolated during 2000 and 2001 from patients presenting with different disease severity. Sequence data were used in phylogenetic comparisons with global samples of DENV-3. Analysis revealed that the strain circulating in Venezuela is closely related to isolates that were previously present in Panama and Nicaragua in 1994 and since then have spread through Central American countries and Mexico. This study also confirms previous reports showing that the DENV-3 strain currently circulating in the Americas is related to the strain that caused DHF epidemics in Sri Lanka and India in 1989-1991 (genotype III). Finally, no evidence of the re-emergence of the strain that circulated in Venezuela in the late 1960s and 1970s (genotype V) was found.

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In 2008, dengue virus serotype 4 (DENV-4) emerged in northeastern Peru, causing a large outbreak and displacing DENV-3, which had predominated for the previous 6 years. Phylogenetic analysis of 2008 and 2009 isolates support their inclusion into DENV-4 genotype II, forming a lineage distinct from strains that had previously circulated in the region.

Epidemic outbreaks of dengue fever (DF) were first recorded in Venezuela in 1978 and were followed by the emergence of dengue haemorrhagic fever (DHF) outbreaks in 1989. To gain a better understanding of the nature of these epidemics, the complete envelope (E) gene sequence of 34 Venezuelan dengue type 2 (DEN-2) viruses, isolated between 1997 and 2000 was determined. Of these isolates, 16 were from patients with DF and 17 were from patients diagnosed with DHF. There were no diagnostic sequence differences between them, suggesting that the E gene alone does not determine disease severity. These sequence data were also used in phylogenetic comparisons with a global sample of DEN-2 viruses, including strains collected previously from Venezuela. This analysis revealed that the ancestors of the Venezuelan viruses were Asian in origin, implying that a DEN-2 virus strain from this region was introduced into Venezuela and the wider Caribbean region during the late 1970s or the early 1980s. The phylogenetic trees further indicate that evolution of DEN-2 virus in Venezuela has occurred in situ, with differentiation into a number of distinct but co-circulating lineages, rather than the repeated introduction of new strains from other localities. By incorporating additional sequence data from the virus capsid, premembrane and membrane genes, evidence is provided that a single Venezuelan strain sequenced previously, designated Mara4, is a recombinant virus, incorporating genome sequence from Venezuelan and Asian parental viruses.

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