title: Peripheral Organs of Dengue Fatal Cases Present Strong Pro-Inflammatory Response with Participation of IFN-Gamma-, TNF-Alpha- and RANTES-Producing Cells.
abstract: Dengue disease is an acute viral illness caused by dengue virus (DENV) that can progress to hemorrhagic stages leading to about 20000 deaths every year worldwide. Despite many clinical investigations regarding dengue, the immunopathogenic process by which infected patients evolve to the severe forms is not fully understood. Apart from differences in virulence and the antibody cross reactivity that can potentially augment virus replication, imbalanced cellular immunity is also seen as a major concern in the establishment of severe dengue. In this context, the investigation of cellular immunity and its products in dengue fatal cases may provide valuable data to help revealing dengue immunopathogenesis. Here, based in four dengue fatal cases infected by the serotype 3 in Brazil, different peripheral organs (livers, lungs and kidneys) were studied to evaluate the presence of cell infiltrates and the patterns of local cytokine response. The overall scenario of the studied cases revealed a considerable systemic involvement of infection with mononuclear cells targeted to all of the evaluated organs, as measured by immunohistochemistry (IHC). Quantification of cytokine-expressing cells in peripheral tissues was also performed to characterize the ongoing inflammatory process by the severe stage of the disease. Increased levels of IFN-γ- and TNF-α-expressing cells in liver, lung and kidney samples of post-mortem subjects evidenced a strong pro-inflammatory induction in these tissues. The presence of increased RANTES-producing cell numbers in all analyzed organs suggested a possible link between the clinical status and altered vascular permeability. Co-staining of DENV RNA and IFN-γ or TNF-α using in situ hibridization and IHC confirmed the virus-specific trigger of the pro-inflammatory response. Taken together, this work provided additional evidences that corroborated with the traditional theories regarding the "cytokine storm" and the occurrence of uneven cellular immunity in response to DENV as major reasons for progress to severe disease.
authors.affiliation: Laboratory of Biotechnology and Physiology of Viral Infections, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Póvoa
authors.affiliation: Laboratory of Molecular Modeling, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Edson R A
authors.initials: ER
authors.lastname: Oliveira
authors.affiliation: Pathological Anatomy, Gaffrée Guinle Hospital, University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Basílio-de-Oliveira
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America.|Phylogeny Inc, Powell, Ohio, United States of America.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.affiliation: Pathological Anatomy, Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil.
authors.forename: Vera L A
authors.initials: VL
authors.lastname: Chagas
authors.affiliation: Interdisciplinary Laboratory of Medical Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Natália G
authors.initials: NG
authors.lastname: Salomão
authors.forename: Ada Maria
authors.initials: AM
authors.lastname: de Barcelos Alves
authors.affiliation: Laboratory of Pathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Mota
authors.affiliation: Interdisciplinary Laboratory of Medical Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Marciano V
authors.initials: MV
authors.lastname: Paes
mesh_terms: D000328:Adult; D018946:Chemokine CCL5 / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D003715:Dengue / Q000150:complications* / Q000276:immunology / Q000401:mortality; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma