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      Gene Expression Patterns of Dengue Virus-Infected Children from Nicaragua Reveal a Distinct Signature of Increased Metabolism

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          Abstract

          Background

          Infection with dengue viruses (DENV) leads to a spectrum of disease outcomes. The pathophysiology of severe versus non-severe manifestations of DENV infection may be driven by host responses, which could be reflected in the transcriptional profiles of peripheral blood immune cells.

          Methodology/Principal Findings

          We conducted genome-wide microarray analysis of whole blood RNA from 34 DENV-infected children in Nicaragua collected on days 3–6 of illness, with different disease manifestations. Gene expression analysis identified genes that are differentially regulated between clinical subgroups. The most striking transcriptional differences were observed between dengue patients with and without shock, especially in the expression of mitochondrial ribosomal proteins associated with protein biosynthesis. In the dengue hemorrhagic fever patients, one subset of differentially expressed genes encode neutrophil-derived anti-microbial peptides associated with innate immunity. By performing a meta-analysis of our dataset in conjunction with previously published datasets, we confirmed that DENV infection in vivo is associated with large changes to protein and nucleic acid metabolism. Additionally, whereas in vitro infection leads to an increased interferon signature, this was not consistently observed from in vivo patient samples, suggesting that the interferon response in vivo is relatively transient and was no longer observed by days 3–6 of illness.

          Conclusions/Significance

          These data highlight important differences between different manifestations of severity during DENV infection as well as identify some commonalities. Compilation of larger datasets in the future across multiple studies, as we have initiated in this report, may well lead to better prediction of disease manifestation via a systems biology approach.

          Author Summary

          Dengue is a widespread viral disease for which over 3 billion people are at risk. There are no drug treatments or vaccines available for this disease. It is also difficult for physicians to predict which patients are at highest risk for the severe manifestations known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). We used genome-wide transcriptional profiling analysis to study peripheral blood responses to dengue among patients from Nicaragua. We found that patients with severe manifestations involving shock had very different transcriptional profiles from dengue patients with mild and moderate illness. We then compared our results with other microarray experiments on dengue patients available from public databases and confirmed that dengue is often associated with large changes to the metabolic processes within cells. This approach could identify prognostic markers for severe dengue as well as provide a better understanding of the pathophysiology associated with different grades of disease severity.

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          Most cited references 31

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          Defensins: antimicrobial peptides of innate immunity.

           Tomas Ganz (2003)
          The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.
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            Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

            A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
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              Global Spread and Persistence of Dengue

              Dengue is a spectrum of disease caused by four serotypes of the most prevalent arthropod-borne virus affecting humans today, and its incidence has increased dramatically in the past 50 years. Due in part to population growth and uncontrolled urbanization in tropical and subtropical countries, breeding sites for the mosquitoes that transmit dengue virus have proliferated, and successful vector control has proven problematic. Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have expanded from South and Southeast Asia into the Pacific and the Americas. This review explores the human, mosquito, and viral factors that contribute to the global spread and persistence of dengue, as well as the interaction between the three spheres, in the context of ecological and climate changes. What is known, as well as gaps in knowledge, is emphasized in light of future prospects for control and prevention of this pandemic disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                June 2010
                15 June 2010
                : 4
                : 6
                Affiliations
                [1 ]Department of Medical Parasitology, School of Medicine, New York University, New York, New York, United States of America
                [2 ]Sustainable Sciences Institute, Managua, Nicaragua
                [3 ]Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America
                [4 ]Unidad de Infectología, Hospital Infantil Manuel Jesús de Rivera, Managua, Nicaragua
                [5 ]Departamento de Virología, Centro Nacional de Diagóstico y Referencia, Ministerio de Salud, Managua, Nicaragua
                [6 ]Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, United States of America
                Centers for Disease Control and Prevention, United States of America
                Author notes

                Conceived and designed the experiments: PL SNH EH. Performed the experiments: PL SNH JML. Analyzed the data: PL JML CCK SB EH. Contributed reagents/materials/analysis tools: PL SNH CR AB. Wrote the paper: PL EH.

                Article
                09-PNTD-RA-0742R2
                10.1371/journal.pntd.0000710
                2886038
                20559541
                Loke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Infectious Diseases/Neglected Tropical Diseases
                Infectious Diseases/Tropical and Travel-Associated Diseases
                Infectious Diseases/Viral Infections

                Infectious disease & Microbiology

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