Thioaptamer decoy targeting of AP-1 proteins influences cytokine expression and the outcome of arenavirus infections.
Viral haemorrhagic fever (VHF) is caused by a number of viruses, including arenaviruses. The pathogenesis is believed to involve dysregulation of cytokine production. The arenaviruses Lassa virus and Pichinde virus have a tropism for macrophages and other reticuloendothelial cells and both appear to suppress the normal macrophage response to virus infection. A decoy thioaptamer, XBY-S2, was developed and was found to bind to AP-1 transcription factor proteins. The P388D1 macrophage-like cell line contains members of the AP-1 family which may act as negative regulators of AP-1-controlled transcription. XBY-S2 was found to bind to Fra-2 and JunB, and enhance the induction of cytokines IL-6, IL-8 and TNF-alpha, while reducing the binding to AP-1 promoter elements. Administration of XBY-S2 to Pichinde virus-infected guinea pigs resulted in a significant reduction in Pichinde virus-induced mortality and enhanced the expression of cytokines from primary guinea pig macrophages, which may contribute to its ability to increase survival of Pichinde virus-infected guinea pigs. These data demonstrate a proof of concept that thioaptamers can be used to modulate the outcome of in vivo viral infections by arenaviruses by the manipulation of transcription factors involved in the regulation of the immune response.
Fennewald
Susan M
SM
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Scott
Erin P
EP
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Zhang
Lihong
L
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Yang
Xianbin
X
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Aronson
Judith F
JF
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Gorenstein
David G
DG
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Luxon
Bruce A
BA
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Shope
Robert E
RE
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Beasley
David W C
DWC
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Barrett
Alan D T
ADT
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
Herzog
Norbert K
NK
Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA.
D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001117:Arenaviridae Infections / Q000276:immunology*; D018050:Arenavirus; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D006168:Guinea Pigs; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013552:Swine; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D052157:Aptamers, Nucleotide; D016207:Cytokines; D051921:Fos-Related Antigen-2; D007155:Immunologic Factors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D004247:DNA; D011070:Poly I-C