Abstract
Andes virus (ANDV) causes hantavirus pulmonary syndrome (HPS), a severe acute disease with a 40% case fatality rate. Humans are infected via inhalation, and the lungs are severely affected during HPS, but little is known regarding the effects of ANDV-infection of the lung. Using a 3-dimensional air-exposed organotypic human lung tissue model, we analyzed progeny virus production and cytokine-responses after ANDV-infection. After a 7–10 day period of low progeny virus production, a sudden peak in progeny virus levels was observed during approximately one week. This peak in ANDV-production coincided in time with activation of innate immune responses, as shown by induction of type I and III interferons and ISG56. After the peak in ANDV production a low, but stable, level of ANDV progeny was observed until 39 days after infection. Compared to uninfected models, ANDV caused long-term elevated levels of eotaxin-1, IL-6, IL-8, IP-10, and VEGF-A that peaked 20–25 days after infection, i.e., after the observed peak in progeny virus production. Notably, eotaxin-1 was only detected in supernatants from infected models. In conclusion, these findings suggest that ANDV replication in lung tissue elicits a late proinflammatory immune response with possible long-term effects on the local lung cytokine milieu. The change from an innate to a proinflammatory response might be important for the transition from initial asymptomatic infection to severe clinical disease, HPS.
Highlights
Hantaviruses are the etiological agents of two severe zoonotic diseases, hantavirus pulmonary syndrome (HPS, called hantavirus cardio-pulmonary syndrome, HCPS) in the Americas, PLOS ONE | DOI:10.1371/journal.pone.0149354 February 23, 2016Andes Virus Infection of a 3D Human Lung Tissue Model collection and analysis, decision to publish, or preparation of the manuscript
These findings suggest that Andes virus (ANDV) affects the local lung tissue cytokine milieu, thereby causing a proinflammatory state that might contribute to the-pathogenesis of HPS
ANDV-infection of the air-exposed 3-dimensional organotypic human lung tissue model resulted in a one-week peak in progeny virus production that coincided in time with a transient innate immune response, which in turn was followed by long-term increased eotaxin-1, IL-6, IL-8, IP-10 and VEGF-A, and decreased RANTES, levels
Summary
The human lung fibroblast cell line MRC-5 (ATCC CCL-171) were grown in Minimum Essential Medium (MEM) supplemented with 10% FBS, 100 U of penicillin/ml and 100 μg of streptomycin/ml. The human bronchial epithelial cell line 16HBE14o- [18], a kind gift from Dr Dieter Gruenert, Mt. Zion Cancer Center, University of California, San Francisco, CA, were grown in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10% FBS, 1% HEPES, 1% non-essential amino acids, 100 U of penicillin/ml and 100 μg of streptomycin/ml. ANDV was propagated and titrated on Vero E6 cells (ATCC Vero C1008) as previously described [19]. The lower limit of detection in the titration assay [19] is 5 focus forming units (FFU) per ml (FFU/ml)
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