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J. Virol. doi:10.1128/JVI.00313-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Dengue virus (DV) replication in monocyte-derived-macrophages is not affected by TNF-, and DV infection induces altered responsiveness to TNF- stimulation

School of Molecular and Biomedical Science, University of Adelaide, SA 5005, Australia; Infectious Diseases laboratories, Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia

^* To whom correspondence should be addressed. Email: satiya.wati{at}imvs.sa.gov.au.

	Abstract

Tumour necrosis factor alpha (TNF-) is believed to play a significant role in the pathogenesis of dengue virus (DV) infection with elevated levels of TNF- in the sera of DV infected patients that parallel the severity of disease and TNF- release is coincident with the peak of DV production from infected monocyte-derived-macrophages (MDM) in vitro. Since macrophages are a primary cell target in vivo for DV infection, we investigated the potential antiviral role of TNF- in regulating DV replication in MDM. While pre-treatment of MDM with TNF- had a minor inhibitory effect, addition of TNF- to MDM with established DV infection had no effect on DV replication as measured by DV RNA levels or progeny virus production. Blocking endogenous TNF- using siRNA or inhibitory TNF- antibodies also had no effect on infectious DV production or viral RNA synthesis. Together, these results demonstrate that DV replication in MDM is not affected by TNF-. Additionally, normal cellular TNF- signalling, measured by quantitation of TNF--induced stimulation of transcription from a NF-kappa B (NF-kB) responsive reporter plasmid or NF-kB protein nuclear translocation, was blocked in DV infected MDM and Huh7 cells. Thus, DV replication in MDM is not affected by TNF-, and infected cells do not respond normally to TNF- stimulation. It is therefore unlikely that the increased production of TNF- seen in DV infection directly effects DV clearance by reducing DV replication and the ability of DV to alter TNF- responsiveness highlights another example of viral subversion of cellular functions.

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