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Are antiviral effects of arsenic trioxide in coxsackievirus B3 infection associated with NFκB and IFN-γ expression in infected mouse tissues?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Today, efficient antiviral drugs targeting acute RNA virus infections, such as coxsackievirus B3 (CVB3) are lacking. Arsenic trioxide (As2O3) was recently found to impair the replication of CVB3 in vitro and in vivo, but it is unknown whether this antiviral effect of As2O3 involves immune-mediated effects. In this study CVB3-infected Balb/c mice were intraperitoneally treated daily with 1 mg As2O3/kg bw for 3, 5 or 7 days. The expression of two genes mediating host defence reactions, nuclear factor κB (NFκB) and interferon γ (IFN-γ), was measured by real-time PCR in the liver, brain and pancreas. In the infected brain As2O3 treatment resulted in an earlier response of IFN-γ, i.e. mice were positive 2 days earlier in the treatment group, but the treatment had no effect on NFκB. In the infected pancreas and liver the expression of both IFN-γ and NFκB remained unaffected by As2O3 treatment. To conclude, As2O3 treatment during infection did not affect NFκB or IFN-γ, except for IFN-γ in the brain. Thus, a reasonable conclusion is that As evolves its antiviral effects mainly by a direct effect on the replication process and to a lesser extent through general host defence-mediated mechanisms.

Keyword [en]
NFκB; IFN-γ; arsenic trioxide; coxsackie B3 infection
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:uu:diva-112045OAI: oai:DiVA.org:uu-112045DiVA: diva2:284472
Available from: 2010-01-07 Created: 2010-01-07 Last updated: 2010-01-07
In thesis
1. Arsenic Influences Virus Replication in Experimental Coxsackievirus B3 Infection
Open this publication in new window or tab >>Arsenic Influences Virus Replication in Experimental Coxsackievirus B3 Infection
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Trace elements are essential for the host defence against infections, and during common infections, the balance of trace elements is changed in serum and tissues. Supplementation with selenium (Se), an essential trace element, is known to decrease the severity of coxsackievirus B3 (CVB3) infection in mice. Even the non-essential trace element arsenic (As) seems to influence the replication of some viruses.

During the course of an acute CVB3 infection in mice, Se concentrations decreased in most tissues and were negatively correlated to viral load in our study. However, As concomitantly decreased in most tissues. As has previously been shown to interfere with the balance of essential trace elements. However, in the present study As supplementation in healthy mice resulted in minor effects on seven studied trace elements in serum and tissues. The effects of As supplementation were more pronounced in CVB3-infected mice, with an increase in As, but a decrease in Se in most tissues when compared with non-infected mice.

As supplementation during CVB3 infection in mice decreased viral RNA concentrations in the brain (97%) and pancreas (75%), two of the target organs of this infection. In vitro experiments indicate that As caused an impaired virion assembly or release. In vivo, infection-induced expression of the host defence-associated genes nuclear factor κB (NFκB) and interferon γ (IFN-γ) were unaffected by As supplementation, except for an earlier increase in IFN-γ in the brain.

In conclusion, a clinically relevant dose of As decreased the replication of CVB3 in vitro and in vivo. This antiviral effect in vivo was not related to changes in specific trace elements or in the host’s immune-mediated defence. Although the mechanism underlying the observed effect on viral replication remains to be further elucidated, As seems to be an intriguing trace element to study in the pursuit of new antiviral drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 513
Keyword
coxsackievirus B3, trace elements, arsenic, selenium, virology, IFN-γ, NFκB
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-112049 (URN)978-91-554-7702-8 (ISBN)
Public defence
2010-02-19, Hörsalen, Klinisk mikrobiologi, Akademiska sjukhuset, ingång D1, Dag Hammarskjölds väg 17, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2010-01-28 Created: 2010-01-07 Last updated: 2010-01-28Bibliographically approved

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