Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma.

Fábio Alves Olímpio,Fellipe Souza Da Silva Vilacoert,Raimunda Do Socorro Da Silva Azevedo,Arnaldo Jorge Martins Filho,Jorge Rodrigues De Sousa,Vanessa Costa Alves Galúcio,Lais Carneiro Dos Santos,Jeferson Da Costa Lopes,Lívia Caricio Martins,Carlos Augusto Moreira Da Silva,Vanessa Do Socorro Cabral Miranda,Ana Cecília Ribeiro Cruz,Juarez Antônio Simões Quaresma,Luiz Fábio Magno Falcão,Marcos Luiz Gaia Carvalho,Maria Irma Seixas Duarte,Pedro Fernando Da Costa Vasconcelos,Caio Cesar Henriques Mendes

doi:10.3390/pathogens11010101

Abstract

Yellow fever (YF) is a pansystemic disease caused by the yellow fever virus (YFV), the prototype species of the family Flaviviridae and genus Flavivirus, and has a highly complex host-pathogen relationship, in which endothelial dysfunction reflects viral disease tropism. In this study, the in situ endothelial response was evaluated. Liver tissue samples were collected from 21 YFV-positive patients who died due to the disease and five flavivirus-negative controls who died of other causes and whose hepatic parenchyma architecture was preserved. Immunohistochemical analysis of tissues in the hepatic parenchyma of YF cases showed significantly higher expression of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and very late antigen-4 in YFV-positive cases than in flavivirus-negative controls. These results indicate that endothelium activation aggravates the inflammatory response by inducing the expression of adhesion molecules that contribute to the rolling, recruitment, migration, and construction of the inflammatory process in the hepatic parenchyma in fatal YF cases.

Highlights

Yellow fever (YF) is a mosquito-borne disease caused by the yellow fever virus (YFV), an arbovirus belonging to the family Flaviviridae and genus Flavivirus
The inflammatory infiltrate was found in large quantities in the portal tract (PT) and in a smaller amount in the acini, with disproportionate intensity to the degree of impairment of the liver parenchyma, being more intense in zone 2 (Z2)
Z3, Z2, Z1, and PT in the hepatic parenchyma of fatal cases affected by YFV and control. (A) Area of necrosis with haemorrhagic foci in A-Z3, A-Z2, and A-Z1

Summary

Introduction

Yellow fever (YF) is a mosquito-borne disease caused by the yellow fever virus (YFV), an arbovirus belonging to the family Flaviviridae and genus Flavivirus. YF is considered the original viral haemorrhagic fever that induces a pansystemic response in severe clinical presentations [3,4]. The pathophysiological processes determining the clinical course of the disease depend on the viral properties and immune response pattern of the host, which can determine the appearance of severe lesions in various organs and tissues, such as the liver, heart, kidneys, and vascular endothelium. Histopathological changes are induced by the direct viral cytopathic effect through changes in the sinusoidal microvasculature and tissue immune response [5,6,7]

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Conclusion