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Protective role of host aquaporin 6 against Hazara virus, a model for Crimean–Congo hemorrhagic fever virus infection
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
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2016 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 363, no 8, fnw058Article in journal (Refereed) PublishedText
Abstract [en]

Crimean–Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne pathogen that causes infectious disease with severe hemorrhagic manifestations in vascular system in humans. The proper function of the cells in the vascular system is critically regulated by aquaporins (AQP), water channels that facilitate fluxes of water and small solutes across membranes. With Hazara virus as a model for CCHFV, we investigated the effects of viruses on AQP6 and the impact of AQP6 on virus infectivity in host cells, using transiently expressed GFP-AQP6 cells, immunofluorescent assay for virus detection, epifluorescent imaging of living cells and confocal microscopy. In GFP-AQP6 expressing cells, Hazara virus reduced both the cellular and perinuclear AQP6 distribution and changed the cell area. Infection of human cell with CCHFV strain IbAR 10200 downregulated AQP6 expression at mRNA level. Interestingly, the overexpression of AQP6 in host cells decreased the infectivity of Hazara virus, speaking for a protective role of AQP6. We suggest the possibility for AQP6 being a novel player in the virus–host interactions, which may lead to less severe outcomes of an infection.

Place, publisher, year, edition, pages
Oxford University Press, 2016. Vol. 363, no 8, fnw058
Keyword [en]
Host–virus interactions; Nairovirus; Crimean–Congo hemorrhagic fever virus; aquaporin; virus infectivity; water homeostasis
National Category
Cell and Molecular Biology Microbiology in the medical area
URN: urn:nbn:se:liu:diva-127499DOI: 10.1093/femsle/fnw058ISI: 000377970600013PubMedID: 26976854OAI: diva2:924422
Swedish Research Council, 2010-3045European Science Foundation (ESF)Magnus Bergvall FoundationSwedish Research Council, 214–7495Linköpings universitet

Funding agencies: Swedish Research Council [2010-3045]; European Science foundation; Magnus Bergvall Foundation; Faculty of Medicine and Health Sciences, Linkoping University; Infect-ERA Second Call (Swedish Research Council) [214-7495]

Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-07-13Bibliographically approved
In thesis
1. Aquaporins in Infection and Inflammation
Open this publication in new window or tab >>Aquaporins in Infection and Inflammation
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ability of eukaryotic cells to change their shape and to migrate directionally is highly dependent on active volume regulation in cells building up tissues as well as in individual cells. Transmembrane fluxes of water via specialized water channels, called aquaporins (AQPs), facilitate the changes of volume and shape, which additionally require a complex interplay between the plasma membrane and the cytoskeleton. AQPs have been shown to be involved in the development of inflammatory processes and diseases. The aims of the studies underlying this thesis were to further elucidate the expression and function of AQPs in both bacterial and viral infections as well as in the inflammatory disease, microscopic colitis. For this, molecular techniques qPCR, immunoblotting and live, holographic, confocal and super-resolution imaging were used.

When cells of the innate immune system encounter pathogens they need to respond and prepare for migration and phagocytosis and do so through volume regulatory processes. The Gramnegative bacterium Pseudomonas aeruginosa utilizes a small molecule-based communication system, called quorum sensing (QS) to control the production of its virulence factors and biofilms. We found that P. aeruginosa with a complete QS system elicits a stronger phagocytic response in human blood-derived macrophages compared to its lasI-/rhlI- mutant lacking the production of the QS molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL). Infection with P. aeruginosa further increases the expression of AQP9 and induces re-localisation of AQP9 to the front and trailing ends of macrophages. Moreover, the 3O-C12-HSL alone elevates the expression of AQP9, redistribute the water channel to the front and rear ends and increases the cell area and volume of macrophages. Both infection with the wild type P. aeruginosa and the treatment with 3OC12-HSL change the nano-structural architecture of the AQP9 distribution in macrophages.

Viruses use the intracellular machinery of the invaded cells to produce and assemble new viral bodies. Intracellular AQPs are localised in a membranes of cellular organelles to regulate their function and morphology. C3H10T1/2 fibroblasts transiently expressing green fluorescent protein (GFP)-AQP6 show a reduced expression of AQP6 after Hazara virus infection and an increased cell area. Overexpressing AQP6 in C3H10T1/2 cells reduces the infectivity of Hazara virus indicating that AQP6 expression has a protective role in virus infections.

Ion and water channels in the epithelial cell lining tightly regulate the water homeostasis. In microscopic colitis (MC), patients suffer from severe watery diarrhoeas. For the first time, we have shown that the expression of AQP1, 8 and 11 and the sodium/hydrogen exchanger NHE1 are reduced in colonic biopsies from MC patients compared to healthy control individuals. Following treatment with the glucocorticoid budesonide the patients experienced a rapid recovery and we observed a restored or increased expression of the AQPs and NHE1 during treatment, suggesting a role for AQPs in the diarrhoeal mechanisms in MC.

Taken together, this thesis provides new evidence on the importance of water homeostasis regulation through AQPs during infections and inflammation and opens up a door for further investigations of roles for AQPs in inflammatory processes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. 58 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1520
National Category
Public Health, Global Health, Social Medicine and Epidemiology Clinical Laboratory Medicine Cell and Molecular Biology
urn:nbn:se:liu:diva-127500 (URN)10.3384/diss.diva-127500 (DOI)978-91-7685-792-2 (Print) (ISBN)
Public defence
2016-06-02, Hasselqvistsalen, Campus US, Linköping, 09:00 (Swedish)
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2016-04-28Bibliographically approved

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