Downloaded from www.microbiologyresearch.org by IP: 54.70.40.11 On: Sun, 11 Nov 2018 18:02:55 Thioaptamer decoy targeting of AP-1 proteins influences cytokine expression and the outcome of arenavirus infections Susan M. Fennewald, 1,2 Erin P. Scott, 1,2 4 Lihong Zhang, 1,2 Xianbin Yang, 3 Judith F. Aronson, 1,2 David G. Gorenstein, 3 Bruce A. Luxon, 3 Robert E. Shope, 1,2 3 David W. C. Beasley, 1,2 Alan D. T. Barrett 1,2 and Norbert K. Herzog 1,2 Correspondence Norbert K. Herzog nherzog@utmb.edu 1 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA 2 Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA 3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0609, USA Received 25 August 2006 Accepted 10 November 2006 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-a, 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. INTRODUCTION Members of the family Arenaviridae (genus Arenavirus) are small RNA viruses that include the prototype Lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PICV) that is non-pathogenic for humans, and highly pathogenic viruses that cause viral haemorrhagic fevers (VHF), including Lassa fever and Argentine, Venezuelan and Bolivian haemorrhagic fevers. Although arenaviruses infect macrophages and dendritic cells, the immune response to arenavirus infec- tions is poorly understood and, as with many of the viruses causing VHF, it is unclear how these viruses evade the immune system or cause death with only limited cellular damage. Our laboratory has been using PICV to study the effects on the immune response of both lethal and non- lethal arenavirus infection of guinea pigs. Increases in TNF-a have been associated with fatal PICV infection of guinea pigs (Aronson et al., 1995), but only in the late stages of infection. Alternatively, there is evidence that swift elaboration of pro- inflammatory cytokines and early engagement of the innate immune response may help protect an infected host from lethal haemorrhagic fever (Baize et al., 1999; Peters et al., 1987; Leroy et al., 2000; Fisher-Hoch et al., 1988). We have been interested in developing strategies to interfere with the pathogenic sequence, or even boost early protective innate immune responses. Members of the AP-1 family of transcription factors are key regulators of a wide range of cellular processes including cell proliferation, cell death, cell differentiation, oncogenesis, inflammation and innate immune responses (Adcock, 1997). While not as strongly associated with the immune response as the NF-kB family of transcription factors, it is still involved in the transcriptional regulation of T-cell receptor alpha (Giese et al., 1995), beta-interferon (IFN-b) (Du et al., 1993; Merika et al., 1998; Thanos & Maniatis, 3Dr Robert E. Shope died 19 January 2004 in Galveston. 4Present address: Department of Microbiology, University of Pennsyl- vania, Philadelphia, PA 19104, USA. 0008-2499 G 2007 SGM Printed in Great Britain 981 Journal of General Virology (2007), 88, 981–990 DOI 10.1099/vir.0.82499-0