KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

John Ziebuhr

Prof. Dr. med. John Ziebuhr

Justus Liebig University
Institute of Medical Virology
Schubertstrasse 81; 35392 Giessen

Michael Kracht

Prof. Dr. med. Michael Kracht

Justus Liebig University
Rudolf Buchheim Institute of Pharmacology
Schubertstrasse 81; 35392 Giessen


Virus-host interactions that drive and control airway epithelial injury in coronavirus infections


Coronaviruses (CoVs) are a major cause of respiratory tract infections in humans. Lung pathology varies greatly between infections caused by common human CoVs (e.g., HCoV-229E) and zoonotic CoVs (e.g., MERS-CoV). The underlying mechanisms for strain-specific differences in human CoV-induced pathology remain poorly understood. The project aims to define CoV-regulated pathways and molecules and their interactions with CoV-encoded effectors in the lung to provide a framework for developing novel therapeutic strategies to treat coronaviral infections more effectively. Using advanced methods, including human lung cell culture systems, CoV reverse genetics, transcriptomics and single cell mRNA and protein-protein interaction analyses we were able to show that HCoV-229E induces a profound and genome-wide host response through NF-κB-dependent and -independent pathways that differ from classical cytokine-driven inflammatory responses. The data obtained in the first funding period suggest that CoVs fine-tune both the NF-κB system and the unfolded protein response (UPR) in a unique (and virus strain-specific) manner, which prompted us to evaluate the effects of inhibitors directed at NF-κB or the UPR in CoV-infected cells. Second, we determined the cellular lipidome of CoV-infected cells and identified (upregulated) specific lysophospholipids as important host cell factors that are required for the formation of intracellular membrane structures necessary for viral RNA synthesis. Third, we investigated CoV replicase gene-encoded enzymatic functions and established their involvement in (i) evading antiviral host reponses in human cells and/or (ii) modulating the cellular transcriptome. Fourth, we found that an alphacoronavirus-wide conserved accessory protein (called ap4 in HCoV-229E) modulates specific cellular pathways. In the next funding period, we will further define the functional interactions of specific CoV proteins with cellular pathways using HCoV-229E and MERS-CoV mutants lacking non-essential activities (Aim 1). To expand our analysis of human CoV strain-specific differences, we will systematically compare specific human lung cell types infected with HCoV-229E and MERS-CoV, focusing on differences in (i) viral replication, (ii) viral and cellular genome expression, and (iii) cell tropism (Aim 2). To reveal CoV strain-specific differences at the level of signaling and to explore the therapeutic potential of small molecule inhibitors, we will investigate the activation and interactions of PERK and NF-κB pathway components at the protein level (Aim 3). Collectively, these approaches will allow us to evaluate comprehensively our central hypothesis that human CoVs evolved a set of proteins that shape and thereby dampen (parts of) the virus-induced host cell response. Accordingly, failure to appropriately control and/or balance these mechanisms is expected to cause more severe lung injury in infections caused by (specific strains of) HCoVs.




Thapsigargin: key to new host-directed coronavirus antivirals?

TIPS 2022 Apr 17. doi.10.1016/j.tips.2022.04.004

SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

Heliyon 2022 Mar 1;8(3):e09029. doi: 10.1016/j.heliyon.2022.e09029

Inhibition of SARS-CoV-2 coronavirus proliferation by designer antisense-circRNAs

Nucleic Acids Res 2021 Dec 2;49(21):12502-12516. doi: 10.1093/nar/gkab1096

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19

Immunity 2021 Nov 9;54(11):2650-2669.e14. doi: 10.1016/j.immuni.2021.09.002

Monitoring the Levels of Cellular NF-κB Activation States

Cancers (Basel) 2021 Oct 26;13(21):5351. doi: 10.3390/cancers13215351

Multi-level inhibition of coronavirus replication by chemical ER stress

Nat Commun 2021; 12: 5536, doi: 10.1038/s41467-021-25551-1

SARS-CoV-2 Variants of Interest and Concern naming scheme conducive for global discourse

Nat Microbiol 2021 Jul;6(7):821-823. doi: 10.1038/s41564-021-00932-w

Swarm Learning for decentralized and confidential clinical machine learning

Nature 2021 Jun;594(7862):265-270. doi: 10.1038/s41586-021-03583-3

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV

Nature 2021 Jun;594(7862):246-252. doi: 10.1038/s41586-021-03493-4

Immunoglobulin deficiency as an indicator of disease severity in patients with COVID-19

Am J Physiol Lung Cell Mol Physiol 2021 Apr 1;320(4):L590-L599. doi: 10.1152/ajplung.00359.2020

Regulation of Transcription Factor NF-κB in Its Natural Habitat: The Nucleus

Cells 2021 Mar 29;10(4):753. doi: 10.3390/cells10040753

Reprograming of sRNA target specificity by the leader peptide peTrpL in response to antibiotic exposure

Nucleic Acids Res 2021 Mar 18;49(5):2894-2915. doi: 10.1093/nar/gkab093

Hallmarks of Alpha- and Betacoronavirus non-structural protein 7+8 complexes

Sci Adv 2021 Mar 3;7(10):eabf1004. doi: 10.1126/sciadv.abf1004

Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy

Br J Pharmacol 2021 Jan;178(1):54-71. doi: 10.1111/bph.14932

ICTV Virus Taxonomy Profile: Roniviridae

J Gen Virol 2021 Jan;102(1):jgv001514. doi: 10.1099/jgv.0.001514

Differential effects of right and left heart failure on skeletal muscle in rats

J Cachexia Sarcopenia Muscle 2020 Dec;11(6):1830-1849. doi: 10.1002/jcsm.12612

Immunoglobulin Deficiency as an Indicator of Disease Severity in Patients with COVID-19

Am J Physiol Lung Cell Mol 2020 Nov 25. doi 10.1152/ajplung.00359.2020

Mutual regulation of metabolic processes and proinflammatory NF-κB signaling

J Allergy Clin Immunol 2020 Oct;146(4):694-705. doi: 10.1016/j.jaci.2020.07.027

Dynamic mRNP Remodeling in Response to Internal and External Stimuli

Biomolecules 2020 Sep 11;10(9):1310. doi: 10.3390/biom10091310

Chromatin Targeting of HIPK2 Leads to Acetylation-Dependent Chromatin Decondensation

Front Cell Dev Biol 2020 Sep 1;8:852. doi: 10.3389/fcell.2020.00852

HDAC3 functions as a positive regulator in Notch signal transduction

Nucleic Acids Res 2020 Apr 17;48(7):3496-3512. doi: 10.1093/nar/gkaa088

SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism

Sci Rep 2020 Feb 10;10(1):2268. doi: 10.1038/s41598-020-59005-3

CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation

J Cell Biol 2019 Apr 1;218(4):1164-1181. doi: 10.1083/jcb.201806057

Characterization of a bafinivirus exoribonuclease activity

J Gen Virol 2018 Sep;99(9):1253-1260. doi: 10.1099/jgv.0.001120

A Single-Center Study of Viral Respiratory Tract Infections in Hospitalized Children From the Kurdistan Region of Iraq

Glob Pediatr Health 2018 Jul 10;5:2333794X18784996. doi: 10.1177/2333794X18784996

PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα

Cancer Res 2018 Apr 1;78(7):1805-1819. doi: 10.1158/0008-5472.CAN-17-1346

Antiviral activity of K22 against members of the order Nidovirales

Virus Res 2018 Feb 15;246:28-34. doi: 10.1016/j.virusres.2018.01.002

Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses

Antiviral Res 2018 Feb;150:123-129. doi: 10.1016/j.antiviral.2017.12.010

Proliferation status defines functional properties of endothelial cells

Cell Mol Life Sci 2017 Apr;74(7):1319-1333. doi: 10.1007/s00018-016-2417-5

Testing the Effects of SIAH Ubiquitin E3 Ligases on Lysine Acetyl Transferases

Methods Mol Biol 2017;1510:297-312. doi: 10.1007/978-1-4939-6527-4_22

Principal Investigators

John Ziebuhr

Prof. Dr. med. John Ziebuhr

Justus Liebig University
Institute of Medical Virology
Schubertstrasse 81; 35392 Giessen

Michael Kracht

Prof. Dr. med. Michael Kracht

Justus Liebig University
Rudolf Buchheim Institute of Pharmacology
Schubertstrasse 81; 35392 Giessen


Project group

  • Knut Beuerlein

    Dr. Knut Beuerlein

    Scientist (AOR)

  • Christin Mayr-Buro

    Dr. Christin Mayr-Buro


  • Christin Müller

    Christin Müller

    PhD student

    +49 - 641 - 99 - 41214
  • Nadja Karl

    Nadja Karl


    +49 - 641 - 99 - 41215
  • Ulrike Wend

    Ulrike Wend