KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

István Vadász

Dr. med. István Vadász

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

Christos Samakovlis

Prof. Dr. Christos Samakovlis

Justus Liebig University
Department of Molecular Pneumology
Aulweg 130; 35392 Giessen


Role and regulation of alveolar protein clearance in influenza virus-induced lung injury


Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) pneumonia and is characterized by disruption of the alveolar epithelial barrier leading to accumulation of protein-rich alveolar edema, which if not resolved promotes deleterious alveolar remodeling leading to poor outcome. Of note, non-survivors of ARDS exhibit three-fold higher levels of protein in their edema fluid than survivors of the disease. However, the molecular mechanisms of alveolar protein removal remain incompletely understood. Importantly, many of the trafficking and repair mechanisms are evolutionary conserved and can be detected in Drosophila airways, which therefore served as a high throughput screening tool. 
In the first funding period, we have been focusing on the mechanisms by which IV infection impairs alveolar protein clearance. We have established and used various in vivo and in vitro model systems, including a mouse model of acute lung injury (ALI) secondary to IV infection, mouse and human three-dimensional precision cut lung slices (PCLS) and a newly established human epithelial air-liquid interface cell culture model allowing IV infection. We have discovered that the TGF β/GSK3 β/megalin axis is markedly compromised upon IV infection, leading to inhibition of alveolar protein clearance in mouse models and, in a translational approach, in human disease, based on sample analyses from patients with IV-induced ARDS. In parallel, we have defined a novel, highly conserved regulatory circuit that centrally controls activation of endocytosis and luminal clearance of macromolecules in Drosophila airways. This circuit involves two type III receptor tyrosine phosphatases (Ptps), the non-receptor tyrosine kinase Btk29A and the actin nucleation-promoting factor Wiskott-Aldrich syndrome protein and SCAR homologue (WASH), the defining member of a protein complex required for endosomal vesicle traffic. Most importantly, the Btk/WASH system appears to be centrally involved in uptake of IV particles in both murine and human epithelial cells. As both propagation of IV infection and clearance of protein-rich pulmonary edema secondary to IV-induced lung damage are mediated by alveolar epithelial endocytic processes, we aim to specifically and selectively target each endocytic process in the upcoming funding period. We envision to inhibit epithelial viral entry by blocking the Btk/WASH cascade, while upregulating protein clearance by interfering with distal elements of the TGF β/GSK3 β/megalin axis. Moreover, we aim to identify putative regulators of the endocytic routes driving IV and protein uptake and manipulate them in translationally relevant model systems that we established during the first funding period. Ultimately, we envision defining novel therapeutic strategies to selectively inhibit viral uptake and spread while improving alveolar clearance of excess protein and thereby the outcome in IV-ARDS.


Correction: Yorkie controls tube length and apical barrier integrity during airway development

J Cell Biol 2023 May 1;222(5):e20180912104072023c. doi: 10.1083/jcb.20180912104072023c

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

Nat Cell Biol 2023 Feb;25(2):351-365. doi: 10.1038/s41556-022-01064-x

Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples

Nat Commun 2023 Jan 31;14(1):509. doi: 10.1038/s41467-023-36071-5

Long-term comprehensive cardiopulmonary phenotyping of COVID-19

Respir Res 2022 Sep 21;23(1):263. doi: 10.1186/s12931-022-02173-9

The discovAIR project: a roadmap towards the Human Lung Cell Atlas

Eur Respir J 2022 Aug 18;60(2):2102057. doi: 10.1183/13993003.02057-2021

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics

Eur J Epidemiol 2022 Aug;37(8):849-870. doi: 10.1007/s10654-022-00896-z

Editorial: Elevated Carbon Dioxide Sensing and Physiologic Effects

Front Physiol 2022 Apr 27;13:894222. doi: 10.3389/fphys.2022.894222

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

A novel non-invasive and echocardiography-derived method for quantification of right ventricular pressure-volume loops

Eur Heart J Cardiovasc Imaging 2022 Mar 22;23(4):498-507. doi: 10.1093/ehjci/jeab038

Unmasking right ventricular-arterial uncoupling during fluid challenge in pulmonary hypertension

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

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

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension

Am J Physiol Lung Cell Mol Physiol 2021 May 1;320(5):L715-L725. doi: 10.1152/ajplung.00583.2020

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

Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Nat Med 2021 Mar;27(3):546-559. doi: 10.1038/s41591-020-01227-z

A comparison of airway pressures for inflation fixation of developing mouse lungs for stereological analyses

Histochem Cell Biol 2021 Feb;155(2):203-2014. doi 10.1007/s00418-020-01951-0

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

SCRINSHOT enables spatial mapping of cell states in tissue sections with single-cell resolution

PLoS Biol 2020 Nov 20;18(11):e3000675. doi: 10.1371/journal.pbio.3000675

Severe organising pneumonia following COVID-19

Thorax 2020 Nov 11;thorayjnl-2020-216088. doi: 10.1136/thoraxjnl-2020-216088

Minoxidil Cannot Be Used To Target Lysyl Hydroxylases during Postnatal Mouse Lung Development: A Cautionary Note

J Pharmacol Exp Ther 2020 Dec; 375(3):478-487. doi: 10.1124/jpet.120.000138

Elevated FiO2 increases SARS-CoV-2 co-receptor expression in respiratory tract epithelium

Am J Physiol Lung Cell Mol Physiol 2020 Oct 1;319(4):L670-L674. doi: 10.1152/ajplung.00345.2020

Myocyte-Specific Upregulation of ACE2 in Cardiovascular Disease: Implications for SARS-CoV-2-Mediated Myocarditis

Circulation 2020 Aug 18;142(7):708-710. doi: 10.1161/CIRCULATIONAHA.120.047911

Commercially available transfection reagents and negative control siRNA are not inert

Anal Biochem 2020 Oct 1;606:113828. doi: 10.1016/j.ab.2020.113828

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

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

Yorkie controls tube length and apical barrier integrity during airway development

J Cell Biol 2019 Aug 5;218(8):2762-2781. doi: 10.1083/jcb.201809121

Anti-anabolic Effects of Hypercapnia - No Country for Strong Men

Am J Respir Cell Mol Biol 2020 Jan;62(1):8-9. doi: 10.1165/rcmb.2019-0225ED

A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension

Nat Commun 2019 May 13;10(1):2130. doi: 10.1038/s41467-019-10044-z

The role of CD36 in endothelial albumin transcytosis

Am J Physiol Lung Cell Mol Physiol 2019 May 1;316(5):L738-L739. doi: 10.1152/ajplung.00104.2019

Regulation and role of the ER stress transcription factor Chop in alveolar epithelial type-II cells

J Mol Med (Berl) 2019 Jul;97(7):973-990. doi:10.1007/s00109-019-01787-9

Editorial: Cytokine-Ion Channel Interactions in Pulmonary Inflammation

Front Immunol Front Immunol. 2018 Nov 6;9:2598. doi:10.3389/fimmu.2018.02598

Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury

Am J Respir Cell Mol Biol 2017 Nov;57(5):589-602. doi: 10.1165/rcmb.2016-0358OC

Perturbations to lysyl oxidase expression broadly influence the transcriptome of lung fibroblasts

Physiol Genomics 2017 Aug 1;49(8):416-429. doi: 10.1152/physiolgenomics.00026.2017

Keratinocyte growth factor in acute respiratory distress syndrome

Lancet Respir Med 2017 Jun;5(6):459-460. doi: 10.1016/S2213-2600(17)30172-8

Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury

Front Immunol 2017 Jul 4;8:757. doi: 10.3389/fimmu.2017.00757

Stereological monitoring of mouse lung alveolarization from the early post-natal period to adulthood

Am J Physiol Lung Cell Mol Physiol 2017 Jun 1;312(6):L882-L895. doi: 10.1152/ajplung.00492.2016

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

Principal Investigators

István Vadász

Dr. med. István Vadász

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

Christos Samakovlis

Prof. Dr. Christos Samakovlis

Justus Liebig University
Department of Molecular Pneumology
Aulweg 130; 35392 Giessen


Project group

  • Ramesh Kumar Krishnan

    Dr. Ramesh Kumar Krishnan


  • Janine Koepke

    Dr. Janine Koepke


  • Athanasios Physikopoulos

    Dr. Athanasios Physikopoulos


  • Luciana C. Mazzocchi

    Dr. Luciana C. Mazzocchi


  • Vitalii Kryvenko

    Vitalii Kryvenko

    PhD student

  • Andrés Alberro

    Andrés Alberro

    PhD student

  • Florian Michel

    Florian Michel

    PhD student

  • Miriam Wessendorf

    Miriam Wessendorf