KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Friedemann Weber

Prof. Dr. rer. nat. Friedemann Weber

Justus Liebig University, Institute for Virology
Veterinary Medicine Faculty
Schubertstr. 81, 35392 Giessen

+49 641-99-38350
Stefan Bauer

Prof. Dr. rer. nat. Stefan Bauer

Philipps-Universität Marburg
Institute for Immunology
Hans-Meerwein-Str. 3, 35043 Marburg

+49 6421-28-66492

Profiling anti-influenza activities of the pathogen recognition receptor RIG-I: Novel targets for antiviral intervention strategies


Influenza A virus (FLUAV) infections cause substantial morbidity and mortality during seasonal and pandemic outbreaks worldwide. However, currently available antiviral therapeutics are of limited efficacy. RIG-I is a cellular virus sensor recognizing FLUAV 5’ppp-dsRNA structures. Activated, ligand RNA-bound RIG-I switches protein conformation to trigger signaling and upregulation of interferons (IFNs) and other antiviral cytokines. Previously, we showed that RIG-I can exert a direct, signaling-independent, antiviral effect by binding the 5’ppp-dsRNA panhandle of FLUAV and disassembling the polymerase complex of avian FLUAV strains (PB2-627E signature). 

In the first funding period, we generated mutants of RIG-I that can still reduce viral RNA synthesis, but do not trigger induction of potentially harmful cytokines like IFN. We also created mice with such a RIG-I mutation (K271A). Other approaches to exploit the RIG-I antiviral action were also pursued. First, we tested the small molecule Paliperidone, a FDA-approved antipsychotic drug predicted to bind to the influenza A basic polymerase protein 2, PB2. We could show for the FLUAV strain PR/8/34 that Paliperidone mimics the direct antiviral activity of RIG-I as it diminished the binding of PB2 to nucleocapsids and reduced viral RNA synthesis. In search for new RIG-I ligands for therapeutic use, we identified rRNA derived self-RNA fragments generated by RNase digestion such as RNase A, RNase L and IRE1alpha (manuscript in revision). Interestingly, immunostimulatory self-fragments can be generated via the glycolysis intermediate Fructose-1,6-bisphosphate (F16BP) that activates the OAS-RNase L pathway [2]. Consequently, F16BP itself or F16BP enrichment by the Glycerinaldehyd-3-phosphat-Dehydrogenase (GAPDH) inhibitor 3-Chlor-1,2-propanediol (CP) create such RIG-I-ligands, suggesting a possible link between an endogenous intermediate of glycolysis and RNase L activity.

In the new funding period, we will build on these achievements to establish novel approaches for antiviral intervention. We will explore the mechanism of the direct antiviral activity of signaling-inactive RIG-I mutants and attempt to optimize it by defining the minimally required domain and by further modifications. To obtain in vivo evidence, the RIG-I K271A mice will be compared with wt mice and RIG-I KO mice for their potential to counter FLUAV infection. Paliperidone will be applied to a variety of human and avian FLUAV strains in permanent cell lines and in primary human airway cells. A potential involvement of RIG-I and other cellular signaling pathways in the Paliperidone mechanism will be investigated, the combination with RIG-I agonists will be evaluated, and, if promising, its antiviral activity will be optimized by lead compound modifications. We will also investigate the influence of the metabolic state of macrophages on RNase L activation, self-RNA fragment generation and subsequent RIG-I-mediated antiviral activity.


Crimean-Congo haemorrhagic fever virus uses LDLR to bind and enter host cells

Nat Microbiol 2024 Mar 28. doi: 10.1038/s41564-024-01672-3

Identification of Host Factors for Rift Valley Fever Phlebovirus

Viruses 2023 Nov 13;15(11):2251. doi: 10.3390/v15112251

Expression of TMPRSS2 is up-regulated by bacterial flagellin, LPS, and Pam3Cys in human airway cells

Life Sci Alliance 2023 May 19;6(8):e202201813. doi: 10.26508/lsa.202201813

Low-density lipoprotein receptor-related protein 1 (LRP1) as an auxiliary host factor for RNA viruses

Life Sci Alliance 2023 Apr 18;6(7):e202302005. doi: 10.26508/lsa.202302005

Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis

Cell Commun Signal 2023 Mar 28;21(1):65. doi: 10.1186/s12964-023-01086-4

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Science 2023 Feb 10;379(6632):586-591. doi: 10.1126/science.add0875

Dissecting the role of toll-like receptor 7 in pancreatic cancer

Cancer Med 2023 Jan 5. doi: 10.1002/cam4.5606

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

J Exp Med 2023 Jan 2;220(1):e20220829. doi: 10.1084/jem.20220829

Identification of an Optimal TLR8 Ligand by Alternating the Position of 2'-O-Ribose Methylation

Int J Mol Sci 2022 Sep 22;23(19):11139. doi: 10.3390/ijms231911139

Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies

Am Sci Adv 2021 Jun 30;7(27):eabh3032. doi: 10.1126/sciadv.abh3032

The International Virus Bioinformatics Meeting 2022

Viruses 2022 May 5;14(5):973. doi: 10.3390/v14050973

RNA-Cholesterol Nanoparticles Function as Potent Immune Activators via TLR7 and TLR8

Front Immunol 2022 Jan 21;12:658895. doi: 10.3389/fimmu.2021.658895

From mRNA sensing to vaccines

Immunity 2021 Dec 14;54(12):2676-2680. doi: 10.1016/j.immuni.2021.10.018

eIF2B-capturing viral protein NSs suppresses the integrated stress response

Nat Commun Dec 7;12(1):7102. doi: 10.1038/s41467-021-27337-x

Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies

Sci Adv 2021 Jun 30;7(27):eabh3032. doi: 10.1126/sciadv.abh3032

Imaging of SARS-CoV-2 infected Vero E6 cells by helium ion microscopy

Beilstein J Nanotechnol 2021 Feb 2;12:172-179. doi: 10.3762/bjnano.12.13

The Short- and Long-Range RNA-RNA Interactome of SARS-CoV-2

Mol Cell 2020 Dec 17;80(6):1067-1077.e5. doi: 10.1016/j.molcel.2020.11.004

A ribosomal RNA fragment with 2',3'-cyclic phosphate and GTP-binding activity acts as RIG-I ligand

Nucleic Acid Res 2020 Oct 9;48(18):10397-10412. doi: 10.1093/nar/gkaa739

Inhibition of SARS-CoV-2 by type I and type III interferons

J Biol Chem 2020 Oct 9;295(41):13958-13964. doi: 10.1074/jbc.AC120.013788

The SARS-CoV-2 N Protein Is a Good Component in a Vaccine

J Virol 2020 Aug 31;94(18):e01279-20. doi: 10.1128/JVI.01279-20

eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition

mBio 2020 Jul 14;11(4):e00976-20. doi: 10.1128/mBio.00976-20

Noncoding RNA MaIL1 is an integral component of the TLR4-TRIF pathway

Proc Natl Acad Sci U S A 2020 Apr 21;117(16):9042-9053. doi: 10.1073/pnas.1920393117

Structure and function of the Toscana virus cap-snatching endonuclease

Nucleic Acids Res 2019 Nov 18;47(20):10914-10930. doi: 10.1093/nar/gkz838

RNA-DNA hybrids and ssDNA differ in intracellular half-life and toll-like receptor 9 activation

Immunobiology 2019 Nov;224(6):843-851. doi: 10.1016/j.imbio.2019.08.001

The Bacterial Product Violacein Exerts an Immunostimulatory Effect Via TLR8

Sci Rep 2019 Sep 20;9(1):13661. doi: 10.1038/s41598-019-50038-x

Ferreting out viral pathogenesis

Nat Microbiol 2019 Mar;4(3):384-385. doi: 10.1038/s41564-019-0390-0

ADAR1 Is Required for Dendritic Cell Subset Homeostasis and Alveolar Macrophage Function

J Immunol 2019 Feb 15;202(4):1099-1111. doi: 10.4049/jimmunol.180026

Second International Conference on Crimean-Congo Hemorrhagic Fever

Antiviral Res 2018 Feb;150:137-147. doi: 10.1016/j.antiviral.2017.11.019

Conserved RNA structures in the intergenic regions of ambisense viruses

Sci Rep 2017 Nov 30;7(1):16625. doi: 10.1038/s41598-017-16875-4

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses

EMBO J 2017 Jun 14;36(12):1770-1787. doi: 10.15252/embj.201695748

Transcription and replication mechanisms of Bunyaviridae and Arenaviridae L proteins

Virus Res 2017 Apr 15;234:118-134. doi: 10.1016/j.virusres.2017.01.018

Principal Investigators

Friedemann Weber

Prof. Dr. rer. nat. Friedemann Weber

Justus Liebig University, Institute for Virology
Veterinary Medicine Faculty
Schubertstr. 81, 35392 Giessen

+49 641-99-38350
Stefan Bauer

Prof. Dr. rer. nat. Stefan Bauer

Philipps-Universität Marburg
Institute for Immunology
Hans-Meerwein-Str. 3, 35043 Marburg

+49 6421-28-66492

Project group

  • Georgios Panagiotidis

    Georgios Panagiotidis

    +49 641-99-39702
  • Andreas Kaufmann

    Dr. Andreas Kaufmann


  • Benjamin Rupf

    M.Sc. Benjamin Rupf

  • Andreas Schön

    Dr. Andreas Schön