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Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease

2013; Public Library of Science; Volume: 7; Issue: 5 Linguagem: Inglês

10.1371/journal.pntd.0002236

1935-2735

Cornelia A. M. van de Weg, Cláudio Mendes Pannuti, Evaldo Stanislau Affonso de Araújo, Henk‐Jan van den Ham, Arno C. Andeweg, Lucy Santos Vilas Boas, Alvina Clara Félix, Karina I. Carvalho, Andréia Manso de Matos, José Eduardo Levi, Camila Malta Romano, Cristiane C. Centrone, Celia L. de Lima Rodrigues, Expedito José de Albuquerque Luna, Eric C. M. Van Gorp, Albert D. M. E. Osterhaus, B Martina, Esper G. Kallás,

Viral Infections and Vectors

Background Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection. Methods Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of São Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) cluster analysis based on the expression of the quantified cytokines was applied to identify groups of patients with similar cytokine profiles. Markers of microbial translocation were linked to groups with similar clinical disease severity and clusters with similar cytokine profiles. Results Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease. Conclusions The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis.