title: A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis.
abstract: Interleukin-1β (IL-1β), an inflammatory cytokine and IL-1 receptor ligand, has diverse activities in the brain. We examined whether IL-1 signaling contributes to the encephalitis observed in mouse adenovirus type 1 (MAV-1) infection, using mice lacking the IL-1 receptor (Il1r1-/-mice). Il1r1-/-mice demonstrated reduced survival, greater disruption of the blood-brain barrier (BBB), higher brain viral loads, and higher brain inflammatory cytokine and chemokine levels than control C57BL/6J mice. We also examined infections of mice defective in IL-1β production (Pycard-/-mice) and mice defective in trafficking of Toll-like receptors to the endosome (Unc93b1-/-mice). Pycard-/-and Unc93b1-/-mice showed lower survival (similar to Il1r1-/-mice) than control mice but, unlike Il1r1-/-mice, did not have increased brain viral loads or BBB disruption. Based on the brain cytokine levels, MAV-1-infected Unc93b1-/-mice had a very different inflammatory profile from infected Il1r1-/-and Pycard-/-mice. Histological examination demonstrated pathological findings consistent with encephalitis in control and knockout mice; however, intranuclear viral inclusions were seen only in Il1r1-/-mice. A time course of infection of control and Il1r1-/-mice evaluating the kinetics of viral replication and cytokine production revealed differences between the mouse strains primarily at 7 to 8 days after infection, when mice began succumbing to MAV-1 infection. In the absence of IL-1 signaling, we noted an increase in the transcription of type I interferon (IFN)-stimulated genes. Together, these results indicate that IL-1 signaling is important during MAV-1 infection and suggest that, in its absence, increased IFN-β signaling may result in increased neuroinflammation.
  
  
  
  The investigation of encephalitis pathogenesis produced by different viruses is needed to characterize virus and host-specific factors that contribute to disease. MAV-1 produces viral encephalitis in its natural host, providing a good model for studying factors involved in encephalitis development. We investigated the role of IL-1 signaling during MAV-1-induced encephalitis. Unexpectedly, the lack of IL-1 signaling increased the mortality and inflammation in mice infected with MAV-1. Also, there was an increase in the transcription of type I IFN-stimulated genes that correlated with the observed increased mortality and inflammation. The findings highlight the complex nature of encephalitis and suggests that IL-1 has a protective effect for the development of MAV-1-induced encephalitis.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Luiza A
authors.initials: LA
authors.lastname: Castro-Jorge
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Carla D
authors.initials: CD
authors.lastname: Pretto
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Asa B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Carnahan
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA krspin@umich.edu.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Spindler
mesh_terms: D000257:Adenoviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism* / Q000821:virology*; D011992:Endosomes / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D017921:Mastadenovirus / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D051193:Toll-Like Receptors
keywords: IL-1; adenovirus; blood-brain barrier; encephalitis; innate immunity