KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Stephan Becker

Prof. Dr. rer. nat. Stephan Becker

Institute of Virology
Hans-Meerwein-Str. 2; 35043 Marburg

Susanne Herold

Prof. Dr. med. Susanne Herold , PhD


Justus Liebig University
Department of Internal Medicine II
Klinikstr. 33; 35392 Giessen


Targeting immunophilin- and MAPK-associated pathways to inhibit MERS-CoV replication and prevent inflammatory lung injury


The emergence of SARS (Severe Acute Respiratory Syndrome) in 2002 and MERS (Middle East Respiratory Syndrome) in 2012 revealed the potential of coronaviruses to induce severe pneumonia and lung injury with high fatality rates. Since novel highly pathogenic CoV are presumed to represent an emerging threat to humans in future, broad-range, readily-available therapeutics are of utmost importance. Using an established MERS-Coronavirus (MERS CoV) mouse infection model and primary human lung cells, we aim to characterize the antiviral mechanisms of compounds known to block MERS CoV-host interactions by inducing interferon lambda (IFNλ) and targeting immunophilin and downstream MAPK pathways in vitro and in vivo. The final goal is to establish readily-available treatment strategies for current and future emerging infections caused by highly pathogenic human coronaviruses. 

In the first funding period, we investigated the antiviral and lung injury-attenuating properties of Cyclosporin A (CsA) in MERS-CoV infection. We revealed that a CsA-induced, strong antiviral effect was largely mediated by induction of a pronounced type III interferon (IFNλ) response. Elevated IFNλ levels stimulated an IRF1 (interferon regulatory transcription factor 1) - dependent upregulation of interferon stimulated genes (ISG) and strongly attenuated viral growth in vitro, in human primary alveolar epithelial cells ex vivo, and, importantly, in our recently established MERS-CoV mouse model in vivo (Sauerhering et al., unpublished data). In addition, our data indicate that both immunophilin- and MAPK-dependent pathways convey the CsA-induced block of MERS-CoV replication. Interestingly, among various MAPK analyzed, only JNK inhibition led to a significant impairment of MERS-CoV particle release. 

In the upcoming funding period we aim to investigate i) how CsA-stimulated molecular signaling cascades lead to IFNλ induction and investigate whether MERS CoV-developed escape strategies directly counteract the cellular defense mechanisms. We will further ii) investigate putative downstream effectors induced by CsA in MERS-CoV infected respiratory epithelial cells which were previously defined by RNA-Seq analyses. The identified differentially expressed genes, including tetherin, viperin and XAF1, will be evaluated for their suitability as targets for antiviral strategies. Moreover, we will elucidate iii) how JNK impairs MERS-CoV particle egress by characterizing its interplay with host cell factors including cyclophilin A to identify and evaluate novel molecular targets for their therapeutic value in our in vivo and ex vivo infection models. Finally, iv) we will investigate the therapeutic potential of treatment strategies targeting CsA-downstream molecules in MERS-CoV in vivo infection.

The obtained data are expected to reveal immunophilin-targeting antiviral compounds for treatment of MERS-CoV, and potentially further respiratory virus infections in vivo.


Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations

Eur Respir J 2023 Apr 27:2200951. doi: 10.1183/13993003.00951-2022

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness

JCI Insight 2023 Feb 8;8(3):e163150. doi: 10.1172/jci.insight.163150

Self-amplifying RNA vaccine protects mice against lethal Ebola virus infection

Mol Ther 2023 Feb 1;31(2):374-386. doi: 10.1016/j.ymthe.2022.10.011

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing

Viruses 2022 Dec 30;15(1):122. doi: 10.3390/v15010122

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease

J Med Chem 2022 Oct 13;65(19):13328-13342. doi: 10.1021/acs.jmedchem.2c01131

An introduction to the Marburg virus vaccine consortium, MARVAC

PLoS Pathog 2022 Oct 13;18(10):e1010805. doi: 10.1371/journal.ppat.1010805

Assembly and transport of filovirus nucleocapsids

PLoS Pathog 2022 Jul 28;18(7):e1010616. doi: 10.1371/journal.ppat.1010616

Long-COVID – eine neue Herausforderung [Long COVID-a new challenge]

Inn Med (Heidelb) 2022 Aug;63(8):811-812. German. doi: 10.1007/s00108-022-01376-y

Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection, Germany

Emerg Infect Dis 2022 Jul;28(7):1506-1509. doi: 10.3201/eid2807.220425

Quantitation of SARS-CoV-2 neutralizing antibodies with a virus-free, authentic test

PNAS Nexus 2022 May;1(2):pgac045. doi: 10.1093/pnasnexus/pgac045

Cyclosporin A Reveals Potent Antiviral Effects in Preclinical Models of SARS-CoV-2 Infection

Am J Respir Crit Care 2022 Apr 15;205(8):964-968. doi: 10.1164/rccm.202108-1830LE

No substantial preexisting B cell immunity against SARS-CoV-2 in healthy adults

iScience 2022 Mar 18;25(3):103951. doi: 10.1016/j.isci.2022.103951

Structural insight into Marburg virus nucleoprotein-RNA complex formation

Nat Commun 2022 Mar 4;13(1):1191. doi: 10.1038/s41467-022-28802-x

ADAM8 signaling drives neutrophil migration and ARDS severity

JCI Insight 2022 Feb 8; 7(3): e149870, doi: 10.1172/jci.insight.149870

Proteomic landscape of SARS-CoV-2- and MERS-CoV-infected primary human renal epithelial cells

Life Sci Alliance 2022 Feb 2;5(5):e202201371. doi: 10.26508/lsa.202201371

SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis

Cell 2021 Dec 22; 184(26): 6243–6261.e27, doi: 10.1016/j.cell.2021.11.033

Multi-level inhibition of coronavirus replication by chemical ER stress

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

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA-SARS-2-S in preclinical vaccination

Proc Natl Acad Sci U S A 2021 Jul 13;118(28):e2026207118. doi: 10.1073/pnas.2026207118

Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report

Ann Am Thorac Soc 2021 Jul;18(7):1087-1097. doi: 10.1513/AnnalsATS.202102-209ST

Protocol for the generation of murine bronchiolospheres

STAR Protoc 2021 Jun 11;2(2):100594. doi: 10.1016/j.xpro.2021.100594

WASP: a versatile, web-accessible single cell RNA-Seq processing platform

BMC Genomics 2021 Mar 18;22(1):195. doi: 10.1186/s12864-021-07469-6

Validation of a Novel Fgf10Cre–ERT2 Knock-in Mouse Line Targeting FGF10Pos Cells Postnatally

Front Cell Dev Biol 2021 May 13;9:671841. doi: 10.3389/fcell.2021.671841

Acid Aspiration Impairs Antibacterial Properties of Liver Macrophages

Am J Respir Cell Mol Biol 2021 May;64(5):641-643. doi: 10.1165/rcmb.2020-0575LE

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

WASP: a versatile, web-accessible single cell RNA-Seq processing platform

BMC Genomics 2021 Mar 18;22(1):195. doi: 10.1186/s12864-021-07469-6

The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection

iScience 2021 Mar 5;24(4):102266. doi: 10.1016/j.isci.2021.102266

Impact of litter size on survival, growth and lung alveolarization of newborn mouse pups

Ann Anat 2020 Nov;232:151579. doi: 10.1016/j.aanat.2020.151579

Besnoitia besnoiti-driven endothelial host cell cycle alteration

Parasitol Res 2020 Aug;119(8):2563-2577. doi: 10.1007/s00436-020-06744-x

Acute kidney injury and urinary biomarkers in hospitalized patients with coronavirus disease-2019

Nephrol Dial Transplant 2020 Jul 1;35(7):1271-1274. doi: 10.1093/ndt/gfaa162

Update on the "Choosing Wisely" initiative in infectious diseases in Germany

Infection 2020 Jun;48(3):317-321. doi: 10.1007/s15010-020-01400-z

Hexamer phasing governs transcription initiation in the 3'-leader of Ebola virus

RNA 2020 Apr;26(4):439-453. doi: 10.1261/rna.073718.119

Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription

mBio 2020 Feb 25;11(1):e02565-19. doi: 10.1128/mBio.02565-19

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Nat Med 2019 Oct;25(10):1589-1600. doi: 10.1038/s41591-019-0602-4

IRE1 Signaling As a Putative Therapeutic Target in Influenza Virus-induced Pneumonia

Am J Respir Cell Mol Biol 2019 Oct;61(4):537-540. doi: 10.1165/rcmb.2019-0123LE

[Four years after the Ebola crisis : Challenges, experiences, and implications in the German public health context]

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Sep;62(9):1041-1051. German. doi: 10.1007/s00103-019-02995-x

Influenza A Virus Infection Induces Apical Redistribution of Na+, K+-ATPase in Lung Epithelial Cells In Vitro and In Vivo

Am J Respir Cell Mol Biol 2019, Sep;61(3):395-398. doi: 10.1165/rcmb.2019-0096LE.

Update in Lung Infections and Tuberculosis 2018

Am J Respir Crit Care Med 2019 Aug 15;200(4):414-422. doi: 10.1164/rccm.201903-0606UP

Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo

EMBO J 2019 Jun 17;38(12):e102099. doi: 10.15252/embj.2019102099

Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses

J Allergy Clin Immunol 2019 Apr;143(4):1403-1415. doi: 10.1016/j.jaci.2018.07.026

Tetherin Inhibits Nipah Virus but Not Ebola Virus Replication in Fruit Bat Cells

J Virol 2019 Jan 17;93(3):e01821-18. doi: 10.1128/JVI.01821-18

Analysis of the multifunctionality of Marburg virus VP40

J Gen Virol 2018 Dec;99(12):1614-1620. doi: 10.1099/jgv.0.001169

A Fluorescently Labeled Marburg Virus Glycoprotein as a New Tool to Study Viral Transport and Assembly

Cell Stem Cell 2018 Dec 6;23(6):794-805.e4. doi: 10.1016/j.stem.2018.10.011

Fp217 Marburg virus and acute kidney injury

Nephrol Dial Transplant 2018 Nov 1;33(11):2069. doi: 10.1093/ndt/gfy281

Generation of therapeutic antisera for emerging viral infections

NPJ Vaccines 2018 Oct 5;3:42. doi: 10.1038/s41541-018-0082-4

Treatment Options for Carbapenem- Resistant Gram-Negative Infections

Dtsch Arztebl Int 2018 May 21;115(20-21):345-352. doi: 10.3238/arztebl.2018.0345

The molecular tweezer CLR01 inhibits Ebola and Zika virus infection

Antiviral Res 2018 Apr;152:26-35. doi: 10.1016/j.antiviral.2018.02.003

New Lineage of Lassa Virus, Togo, 2016

Emerg Infect Dis 2018 Mar;24(3):599-602. doi: 10.3201/eid2403.171905

Ebola virus proteins NP, VP35, and VP24 are essential and sufficient to mediate nucleocapsid transport

Proc Natl Acad Sci U S A 2018 Jan 30;115(5):1075-1080. doi: 10.1073/pnas.1712263115

Dynamic phosphorylation of Ebola virus VP30 in NP-induced inclusion bodies

Virology 2017 Dec;512:39-47. doi: 10.1016/j.virol.2017.09.006

Structure and assembly of the Ebola virus nucleocapsid

Nature 2017 Nov 16;551(7680):394-397. doi: 10.1038/nature24490

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever

Clin Infect Dis 2017 Sep 1;65(5):855-859. doi: 10.1093/cid/cix406

Control measures following a case of imported Lassa fever from Togo, North Rhine Westphalia, Germany, 2016

Euro Surveill 2017 Sep;22(39):17-00088. doi: 10.2807/1560-7917.ES.2017.22.39.17-00088

The "Choosing Wisely" initiative in infectious diseases

Infection 2017 Jun;45(3):263-268. doi: 10.1007/s15010-017-0997-0

Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization

EBioMedicine 2017 May;19:107-118. doi: 10.1016/j.ebiom.2017.03.045

Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Cell Stem Cell 2017 Feb 2;20(2):261-273.e3. doi: 10.1016/j.stem.2016.10.004. Epub 2016 Nov 17. Erratum in: Cell Stem Cell. 2017 Apr 6;20(4):571

Tamoxifen dosing for Cre-mediated recombination in experimental bronchopulmonary dysplasia

Transgenic Res 2017 Feb;26(1):165-170. doi: 10.1007/s11248-016-9987-8

Comprehensive Characterization of Cellular Immune Responses Following Ebola Virus Infection

J Infect Dis 2017 Jan 15;215(2):287-292. doi: 10.1093/infdis/jiw508

The natural compound silvestrol is a potent inhibitor of Ebola virus replication

Antiviral Res 2017 Jan;137:76-81. doi: 10.1016/j.antiviral.2016.11.011

Marburg virus regulates the IRE1/XBP1-dependent unfolded protein response to ensure efficient viral replication

Emerg Microbes Infect 2019;8(1):1300-1313. doi: 10.1080/22221751.2019.1659552

Live-Cell Imaging of Filoviruses

Methods Mol Biol 2017;1628:195-202. doi: 10.1007/978-1-4939-7116-9_15

Inside the Cell: Assembly of Filoviruses

Curr Top Microbiol Immunol 2017;411:353-380. doi: 10.1007/82_2017_15

Principal Investigators

Stephan Becker

Prof. Dr. rer. nat. Stephan Becker

Institute of Virology
Hans-Meerwein-Str. 2; 35043 Marburg

Susanne Herold

Prof. Dr. med. Susanne Herold , PhD


Justus Liebig University
Department of Internal Medicine II
Klinikstr. 33; 35392 Giessen


Project group

  • Lucie Sauerhering

    Dr. Lucie Sauerhering


  • Hosam Shams-Eldin

    Dr. Hosam Shams-Eldin


  • Alexandra Kupke

    Dr. Alexandra Kupke


  • Lars Meier

    Lars Meier , PhD student

  • Stefanie Jarmer

    Stefanie Jarmer


  • Katharina Kowalski

    Katharina Kowalski