title: Revisiting the liver in human yellow fever: virus-induced apoptosis in hepatocytes associated with TGF-beta, TNF-alpha and NK cells activity.
abstract: Flavivirus infection as dengue and yellow fever persists as a terrible menace to pandemics, due to Aedes prevalence in the Americas. Yellow fever is characterized by hepatocyte damage, with steatosis, apoptosis and necrosis, mainly in the midzonal region of the liver, but the injury mechanism has not been studied at the light of recent knowledge, such as the advances in cell death mechanisms, inflammatory response and cytokine cell expression tools. We studied 53 human liver paraffin embedded blocks from patients who died with yellow fever, all with histological demonstration of higher prevalence of apoptosis over necrosis and mild disproportionate inflammatory response. Viral antigens were found most frequently in hepatocytes from the midzonal area than other lobule areas, as detected by specific immunohistochemistry. Infiltrating cell subpopulations showed mainly CD4+ T lymphocytes, with small numbers of CD8+ cytotoxic lymphocytes, CD20+ B lymphocytes, NKT+ cells and S100+ dendritic cells in the sites of inflammation, as compared to normal and leptospirosis liver blocks. Some cells expressed TNF-alpha and IFN-gamma, but a much more intense proportion of TGF-beta expressing cells were found, suggesting both a Th1 and Th3 patterns of immune response in yellow fever. Most affected hepatocyte presented apoptosis markers that appear at the cell death main pathway in this infection. Viral antigens, which production could interfere in hepatocyte biology, could induce the activation of apoptosis cascade, but TGF-beta was also an apoptosis promoter. Our finding supports the key effect of the yellow fever virus in hepatocyte injury, resulting in prevalence of apoptosis over necrosis, aside from a TGF-beta action induced by the inflammatory response.
authors.affiliation: Tropical Medical Center, Federal do Para University, Av. Generalissimo Deodoro 92, 66055-420 Belem, Para, Brazil. juarez@ufpa.br
authors.forename: Juarez A S
authors.initials: JA
authors.lastname: Quaresma
authors.forename: Vera L R S
authors.initials: VL
authors.lastname: Barros
authors.forename: Carla
authors.initials: C
authors.lastname: Pagliari
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Fernandes
authors.forename: Fernanda
authors.initials: F
authors.lastname: Guedes
authors.forename: Cleusa F H
authors.initials: CF
authors.lastname: Takakura
authors.forename: Heitor F
authors.initials: HF
authors.lastname: Andrade
authors.forename: Pedro F C
authors.initials: PF
authors.lastname: Vasconcelos
authors.forename: Maria I S
authors.initials: MI
authors.lastname: Duarte
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000956:Antigens, Viral / Q000032:analysis; D017209:Apoptosis; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000473:pathology / Q000821:virology*; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D016612:Paraffin Embedding; D016212:Transforming Growth Factor beta / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*; D015004:Yellow Fever / Q000276:immunology / Q000473:pathology* / Q000821:virology; D015005:Yellow fever virus / Q000302:isolation & purification
chemical_list: D000956:Antigens, Viral; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha