title: Andes Hantavirus-Infection of a 3D Human Lung Tissue Model Reveals a Late Peak in Progeny Virus Production Followed by Increased Levels of Proinflammatory Cytokines and VEGF-A.
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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Sundström
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Anh Thu
authors.initials: AT
authors.lastname: Nguyen Hoang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Insitutet, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Shawon
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Clinical Microbiology, Division of Infectious Diseases, Umeå University, Umeå, Sweden.
authors.forename: Clas
authors.initials: C
authors.lastname: Ahlm
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Svensson
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Klingström
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006476:Orthohantavirus / Q000502:physiology*; D018778:Hantavirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008954:Models, Biological; D011024:Pneumonia, Viral / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013577:Syndrome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D016207:Cytokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A