title: Curcumin inhibits Rift Valley fever virus replication in human cells.
abstract: Rift Valley fever virus (RVFV) is an arbovirus that is classified as a select agent, an emerging infectious virus, and an agricultural pathogen. Understanding RVFV-host interactions is imperative to the design of novel therapeutics. Here, we report that an infection by the MP-12 strain of RVFV induces phosphorylation of the p65 component of the NFκB cascade. We demonstrate that phosphorylation of p65 (serine 536) involves phosphorylation of IκBα and occurs through the classical NFκB cascade. A unique, low molecular weight complex of the IKK-β subunit can be observed in MP-12-infected cells, which we have labeled IKK-β2. The IKK-β2 complex retains kinase activity and phosphorylates an IκBα substrate. Inhibition of the IKK complex using inhibitors impairs viral replication, thus alluding to the requirement of an active IKK complex to the viral life cycle. Curcumin strongly down-regulates levels of extracellular infectious virus. Our data demonstrated that curcumin binds to and inhibits kinase activity of the IKK-β2 complex in infected cells. Curcumin partially exerts its inhibitory influence on RVFV replication by interfering with IKK-β2-mediated phosphorylation of the viral protein NSs and by altering the cell cycle of treated cells. Curcumin also demonstrated efficacy against ZH501, the fully virulent version of RVFV. Curcumin treatment down-regulated viral replication in the liver of infected animals. Our data point to the possibility that RVFV infection may result in the generation of novel versions of host components (such as IKK-β2) that, by virtue of altered protein interaction and function, qualify as unique therapeutic targets.
authors: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110, USA.
authors: Aarthi
authors: A
authors: Narayanan
authors: Kylene
authors: K
authors: Kehn-Hall
authors: Svetlana
authors: S
authors: Senina
authors: Lindsay
authors: L
authors: Lundberg
authors: Rachel
authors: R
authors: Van Duyne
authors: Irene
authors: I
authors: Guendel
authors: Ravi
authors: R
authors: Das
authors: Alan
authors: A
authors: Baer
authors: Laura
authors: L
authors: Bethel
authors: Michael
authors: M
authors: Turell
authors: Amy Lynn
authors: AL
authors: Hartman
authors: Bhaskar
authors: B
authors: Das
authors: Charles
authors: C
authors: Bailey
authors: Fatah
authors: F
authors: Kashanchi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012295:Rift Valley Fever / Q000821:virology; D012296:Rift Valley fever virus / Q000378:metabolism*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D051550:I-kappa B Kinase; D003474:Curcumin