Abstract
Kyasanur Forest disease virus (KFDV) is a highly pathogenic tick-borne flavivirus enzootic to India. In humans, KFDV causes a severe febrile disease. In some infected individuals, hemorrhagic manifestations, such as bleeding from the nose and gums and gastrointestinal bleeding with hematemesis and/or blood in the stool, have been reported. However, the mechanisms underlying these hemorrhagic complications remain unknown, and there is no information about the specific target cells for KFDV. We investigated the interaction of KFDV with vascular endothelial cells (ECs) and monocyte-derived dendritic cells (moDCs), which are key targets for several other hemorrhagic viruses. Here, we report that ECs are permissive to KFDV infection, which leads to their activation, as demonstrated by the upregulation of E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 at the mRNA and protein levels. Increased expression of these adhesive molecules correlated with increased leukocyte adhesion. Infected ECs upregulated the expression of interleukin (IL)-6 but not IL-8. Additionally, moDCs were permissive to KFDV infection, leading to increased release of IL-6 and tumor necrosis factor-α. Supernatants from KFDV-infected moDCs caused EC activation, as measured by leukocyte adhesion. The results indicate that ECs and moDCs can be targets for KFDV and that both direct and indirect mechanisms can contribute to EC activation.
Highlights
Introduction KyasanurForest disease (KFD) virus (KFDV) is an emerging tick-borne pathogen and a member of the genus Flavivirus within the family Flaviviridae
To the best of our knowledge, this study reports for the first time that human endothelial cells (ECs) are permissive to Kyasanur Forest disease virus (KFDV) infection, which leads to EC activation, release of interleukin (IL)-6, a marked increase in leukocyte adhesion molecule expression, and increased leukocyte adhesion
KFDV can infect and replicate in human vascular ECs KFDV infection and replication kinetics in Human dermal microvascular ECs (HDMECs) were determined by plaque assay and by immunofluorescence staining for viral antigen
Summary
Forest disease (KFD) virus (KFDV) is an emerging tick-borne pathogen and a member of the genus Flavivirus within the family Flaviviridae. KFDV is prevalent in southern parts of India, where it causes acute hemorrhagic illness in humans and wild nonhuman primates[1,2]. Annual numbers of human cases of KFD range from 400 to 500 in endemic regions, with a case fatality rate of 3–5% (up to 10% during outbreaks); it is believed that these numbers are largely underestimated[2]. KFD resembles Omsk hemorrhagic fever, another tick-borne hemorrhagic disease[5,6]. The incubation period of KFD in people ranges from 3 to 8 d, followed by sudden onset of the first clinical signs, such as chills, severe frontal headache, and fever of >40 °C.
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