title: In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+ Cells upon Thogoto Virus Infection.
abstract: Type I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-α/β) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-α. Unexpectedly, we found robust, systemic IFN-α expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN-α production required in vivo conditions and was not achieved during in vitro infection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b(+) F4/80(+) myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type.
  
  
  
  Type I IFNs are crucial for the survival of a host upon most viral infections, and, moreover, they shape subsequent adaptive immune responses. Production of protective amounts of type I IFN critically depends on the positive feedback amplification via the IFNAR. Unexpectedly, we observed robust IFNAR-independent type I IFN expression upon THOV infection and unraveled molecular mechanisms and determined the tissue and cell type involved. Our data indicate that the host can effectively use alternative pathways to induce type I IFN responses if the classical feedback amplification is not available. Understanding how type I IFN can be produced in large amounts independently of IFNAR-dependent enhancement will identify mechanisms which might contribute to novel therapeutic strategies to fight viral pathogens.
authors: Institute of Virology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Georg
authors: G
authors: Kochs
authors: Junior Research Group, Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.
authors: Martina
authors: M
authors: Anzaghe
authors: Junior Research Group, Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.
authors: Stefanie
authors: S
authors: Kronhart
authors: Institute of Virology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors: Valentina
authors: V
authors: Wagner
authors: Junior Research Group, Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany.
authors: Patricia
authors: P
authors: Gogesch
authors: Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
authors: Stefanie
authors: S
authors: Scheu
authors: Institute for Laboratory Animal Science, Hanover Medical School, and Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hanover, Germany.
authors: Stefan
authors: S
authors: Lienenklaus
authors: Junior Research Group, Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany zoe.waibler@pei.de.
authors: Zoe
authors: Z
authors: Waibler
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000821:virology*; D010537:Peritoneum / Q000378:metabolism / Q000821:virology*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018117:Thogotovirus / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D039481:CD11b Antigen; D007370:Interferon Type I; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta