title: Activation of common antiviral pathways can potentiate inflammatory responses to septic shock.
abstract: Induction 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.
authors.affiliation: Department of Pediatrics and Surgery, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Doughty
authors.forename: Stacey
authors.initials: S
authors.lastname: Carlton
authors.forename: Benjamin
authors.initials: B
authors.lastname: Galen
authors.forename: Indranie
authors.initials: I
authors.lastname: Cooma-Ramberan
authors.forename: Chung-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D016898:Interferon-alpha / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000187:drug effects / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D010529:Peritoneal Cavity / Q000382:microbiology / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014777:Virus Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011070:Poly I-C