• Lesley A Doughty, Stacey Carlton, Benjamin Galen, Indranie Cooma-Ramberan, Chung-Shiang Chung, and Alfred Ayala.
• Department of Pediatrics and Surgery, Rhode Island Hospital, Providence, RI, USA.
• Shock. 2006 Aug 1; 26 (2): 187194187-94.

AbstractInduction of the antiviral cytokine interferon alpha/beta (IFN-alpha/beta) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-alpha/beta inducer as well as nuclear factor kappaB (NF-kappaB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-alpha in serum within 24 h of PIC injection with IFN-alpha/beta-dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-alpha/beta signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-kappaB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide, an NF-kappaB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-alpha induction by PIC. Inhibition of NF-kappaB by parthenolide did reduce IFN-alpha-mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease.

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