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  • 1.
    Kurhade, Chaitanya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Zegenhagen, Loreen
    Weber, Elvira
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Michaelsen-Preusse, Kristin
    Spanier, Julia
    Gekara, Nelson O.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kroeger, Andrea
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-12016In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 13, article id 22Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Weber, Elvira
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Finsterbusch, Katja
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lienenklaus, Stefan
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Gekara, Nelson O
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Janik, Dirk
    Institute of Pathology, Helmholtz Center Munich, Neuherberg, Germany.
    Weiss, Siegfried
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Kalinke, Ulrich
    Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.
    Överby, Anna K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kröger, Andrea
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses2014In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 89, no 21, p. 12202-12212Article in journal (Refereed)
    Abstract [en]

    Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE: The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.

  • 3.
    Weber, Elvira
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Finsterbusch, Katja
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroger, Andrea
    Överby, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Type I interferon protects against lethal Langat virus infection2013In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 63, no 3, p. 308-308Article in journal (Other academic)
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