title: Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1.
abstract: BACKGROUND
  Although type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host.
  
  
  METHODS
  IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed.
  
  
  RESULTS
  We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-β levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS.
  
  
  CONCLUSIONS
  We show that LGTV replication is restricted to the olfactory bulb and that IPS-1 is a very important player in the olfactory bulb in shaping the innate immune response by inhibiting early viral replication and viral spread throughout the central nervous system. In the absence of IPS-1, higher viral replication leads to the evasion of antiviral response by inhibiting interferon signaling. Our data suggest that the local microenvironment of distinct brain regions is critical to determine virus permissiveness.
authors.affiliation: Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Kurhade
authors.affiliation: Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Loreen
authors.initials: L
authors.lastname: Zegenhagen
authors.affiliation: Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.|Present Address: Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
authors.forename: Elvira
authors.initials: E
authors.lastname: Weber
authors.affiliation: Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.|Present Address: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Nair
authors.affiliation: Department of Cellular Neurobiology, Technical University Braunschweig, Braunschweig, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Michaelsen-Preusse
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover Medical School and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors.forename: Nelson O
authors.initials: NO
authors.lastname: Gekara
authors.affiliation: Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.|Institute of Medical Microbiology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Virology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden. anna.overby@umu.se.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Överby
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D004669:Encephalitis Viruses, Tick-Borne / Q000472:pathogenicity*; D004675:Encephalitis, Tick-Borne / Q000473:pathology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D007370:Interferon Type I; C512612:MAVS protein, mouse
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