KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Stephan Becker

Prof. Dr. rer. nat. Stephan Becker

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

+49-6421-28-66253
Christin Peteranderl

Christin Peteranderl , geb. Becker, PhD

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

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

Summary

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cells ex vivo, and, importantly, in our recently established MERS-CoV mouse model in vivo (Sauerhering et al., unpublished data).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.

Publications

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, in press

IRE-1 signaling as a putative therapeutic target in influenza-induced pneumonia

Am J Respir Cell Mol Biol 2019, in press

















Principal Investigators

Stephan Becker

Prof. Dr. rer. nat. Stephan Becker

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

+49-6421-28-66253
Christin Peteranderl

Christin Peteranderl , geb. Becker, PhD

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

Project group

  • Lucie Sauerhering

    Dr. Lucie Sauerhering

    Postdoc

    +49-6421-28-65159
  • Hosam Shams-Eldin

    Dr. Hosam Shams-Eldin

    Veterinarian

  • Alexandra Kupke

    Dr. Alexandra Kupke

    Veterinarian

  • Blanche Nganko

    Blanche Nganko

    MD student

    +49-641-985-42712
  • Stefanie Jarmer

    Stefanie Jarmer

    Technician

    +49-641-985-42712
  • Katharina Kowalski

    Katharina Kowalski

    Technician