KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Natascha Sommer

PD Dr. med, PhD Natascha Sommer

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

Chrysanthi Skevaki

Dr. Chrysanthi Skevaki

Philipps-Universität
Marburg Institute of Laboratory Medicine
Baldingerstraße; 35043 Marburg

+49-6421 28-21443

Mitochondrial T-Cell reprogramming in virus-induced COPD exacerbation/emphysema progression

Summary

Chronic obstructive pulmonary disease (COPD) ranks among the top 3 global causes of death. Virus-induced exacerbations are heavily responsible for the prominent morbidity, mortality and associated health care costs. COPD patients suffer from increased susceptibility to- and decreased clearance from- respiratory viruses, as well as hyperinflammation in response to associated infections, which promotes lung injury and permanent lung remodelling. Enhanced susceptibility and immunopathology have been associated with distorted innate and adaptive immune responses, in particular with the crosstalk of macrophages and bronchial epithelial cells (BEC) with T cells. Mitochondria may be critically involved in this intercellular communication. Induction of the mitochondrial anti-viral signalling protein (MAVS) pathway in macrophages/BEC, mitochondrial localization at the immune synapse, regulation of cellular metabolism and release of mitochondrial reactive oxygen species (mtROS) collectively coordinate T cell activation, proliferation, differentiation and exhaustion. 

We hypothesize that (i) chronic smoke exposure-induced mitochondrial dysfunction (including aberrant mtROS, MAVS) causes impaired T cell function (activation, proliferation, differentiation), which enhances susceptibility to respiratory virus infections in COPD, (ii) recurrent virus infections excessively activate mitochondrial signaling, promote hyperinflammation and T cell exhaustion, and ultimately emphysema and (iii) targeting mitochondrial reprogramming of T cells and mtROS/MAVS-signaling in macrophages/BEC will allow augmentation of antiviral immune responses and prevent disease exacerbations and progression of emphysema. In order to investigate our hypotheses, we aim on: 1) Characterization of smoke-induced mitochondrial alterations affecting T cell activation, proliferation, differentiation and contraction following infection with rhinovirus or influenza A virus in a murine cigarette smoke-induced emphysema model; 2) Determination of the role of mitochondrial pathways (including mtROS, MAVS) in virus-induced progression of emphysema; 3) Pharmacological and genetic interventions addressing pathways as identified in objectives 1 and 2 using in vitro and in vivo short- and long- term smoke exposure and viral infections. Interventions will be achieved by the use of mtROS inhibitors, T cell specific knockout mice and adoptive T cell transfer; 4) Translation to the human context by use of biosamples (peripheral blood mononuclear cells, bronchoalveolar lavage, lung tissue, precision cut lung slices) for molecular biological and functional analysis from control subjects, and COPD patients with or without a virus-induced exacerbation; 5) Transfer of key findings from the murine smoke-induced emphysema model regarding T-cell dysfunction and mitochondrial alterations to an e-cigarette mouse model, in order to investigate potential deleterious effects of e-cigarette vapour (with and without nicotine) on pulmonary immune responses.

Publications

Cellular ROS and Antioxidants: Physiological and Pathological Role

Antioxidants (Basel) 2024 May 14;13(5):602. doi: 10.3390/antiox13050602


[Harmful health effects of flavors in e-cigarettes]

Dtsch Med Wochenschr 2024 May;149(11):646-653. German. doi: 10.1055/a-2260-5003



[Tobacco cessation: one of the most effective medical measures]

Inn Med (Heidelb) 2024 Apr;65(4):365-375. German. doi: 10.1007/s00108-024-01683-6

The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung

Aging Dis 2024 Apr 1;15(2):911-926. doi: 10.14336/AD.2023.0715


[Pulmonary hypertension associated with lung disease]

Pneumologie 2023 Nov;77(11):916-925. German. doi: 10.1055/a-2145-4756

[Genetic diagnostics and molecular approaches in pulmonary arterial hypertension]

Pneumologie 2023 Nov;77(11):862-870. German. doi: 10.1055/a-2145-4663

Pulmonary Hypertension: A Contemporary Review

Am J Respir Crit Care Med 2023 Sep 1;208(5):528-548. doi: 10.1164/rccm.202302-0327SO


The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung

Aging Dis 2023 Jul 27. doi: 10.14336/AD.2023.0715

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD

Am J Respir Crit Care Med 2023 Jun 15;207(12):1576-1590. doi: 10.1164/rccm.202208-1603OC

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

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

Update of ESCMID COVID-19 guidelines: diagnostic testing for SARS-CoV-2

Clin Microbiol Infect 2023 Apr 21:S1198-743X(23)00192-1. doi: 10.1016/j.cmi.2023.04.019

Acute and Chronic Impacts of Heat Stress on Planetary Health

Allergy 2023 Mar 8. doi: 10.1111/all.15702



Antibody Repertoire and Autoimmunity

J Allergy Clin Immunol 2023 Feb 20:S0091-6749(23)00222-1. doi: 10.1016/j.jaci.2023.02.008


Comorbidity defines asthmatic patients' risk of COVID-19 hospitalization: A global perspective

J Allergy Clin Immunol 2023 Jan;151(1):110-117. doi: 10.1016/j.jaci.2022.09.039



IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction

Eur Respir J 2022 Nov 3;60(5):2102130. doi: 10.1183/13993003.02130-2021

Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?

Biochim Biophys Acta Bioenerg 2022 Nov 1;1863(8):148911. doi: 10.1016/j.bbabio.2022.148911



T2-high asthma phenotypes across lifespan

Eur Respir J 2022 Sep 29;60(3):2102288. doi: 10.1183/13993003.02288-2021

Myeloid CD169/Siglec1: An immunoregulatory biomarker in viral disease

Front Med (Lausanne) 2022 Sep 23;9:979373. doi: 10.3389/fmed.2022.979373


Biotin interference can cause false-negative specific IgE results in patients with anaphylaxis

J Allergy Clin Immunol Pract 2022 Sep;10(9):2459-2462.e2. doi: 10.1016/j.jaip.2022.05.021

[Pulmonary manifestations in long COVID]

Inn Med (Heidelb) 2022 Aug;63(8):819-829. German. doi: 10.1007/s00108-022-01371-3




ESCMID COVID-19 guidelines: diagnostic testing for SARS-CoV-2

Clin Microbiol Infect 2022 Jun;28(6):812-822. doi: 10.1016/j.cmi.2022.02.011


Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension

Respir Res 2022 Mar 27;23(1):74. doi: 10.1186/s12931-022-01987-x

SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension

Circulation 2022 Mar 22;145(12):916-933. doi: 10.1161/CIRCULATIONAHA.121.057001

Risk assessment in pulmonary hypertension based on routinely measured laboratory parameters

J Heart Lung Transplant 2022 Mar;41(3):400-410. doi: 10.1016/j.healun.2021.10.018




Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone

Cardiovasc Res 2022 Jan 7;118(1):305-315. doi: 10.1093/cvr/cvaa310

Epidemiology and management of asthma and atopic dermatitis in Sub-Saharan Africa

J Allergy Clin Immunol 2021 Dec;148(6):1378-1386. doi: 10.1016/j.jaci.2021.10.019


Allergen extract- and component-based diagnostics in children of the ALLIANCE asthma cohort

Clin Exp Allergy 2021 Oct;51(10):1331-1345. doi: 10.1111/cea.13964





Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

Eur Respir Rev 2021 Sep 15;30(161):210059. doi: 10.1183/16000617.0059-2021

New-onset IgG autoantibodies in hospitalized patients with COVID-19

Nat Commun 2021 Sep 14;12(1):5417. doi: 10.1038/s41467-021-25509-3

New Avenues for Antiinflammatory Signaling of Nur77 in Acute Lung Injury

Am J Respir Cell Mol Biol 2021 Sep;65(3):236-237. doi: 10.1165/rcmb.2021-0210ED



PINK1-mediated Mitophagy Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension

Am J Respir Cell Mol Biol 2021 Aug;65(2):226-228. doi: 10.1165/rcmb.2021-0082LE

How to interpret and use COVID-19 serology and immunology tests

Clin Microbiol Infect 2021 Jul;27(7):981-986. doi: 10.1016/j.cmi.2021.05.001

Relationship Between Maternal Bone Biomarkers and Fetal Adiposity Through Normal Pregnancy

J Clin Endocrinol Metab 2021 Jun 16;106(7):e2647-e2655. doi: 10.1210/clinem/dgab152

Metabolic Reprogramming in Congenital Cyanotic Heart Disease: Another Fight in Puberty?

Circulation 2021 Jun 8;143(23):2273-2276. doi: 10.1161/CIRCULATIONAHA.121.054217


The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

Am J Physiol Lung Cell Mol Physiol 2021 May 1;320(5):L903-L915. doi: 10.1152/ajplung.00048.2021



SARS-CoV-2 infection and COVID-19 in asthmatics: a complex relationship

Nat Rev Immunol 2021 Apr;21(4):202-203. doi: 10.1038/s41577-021-00516-z


Mitochondrial Monoamine Oxidase: Another Player in Pulmonary Hypertension?

Am J Respir Cell Mol Biol 2021 Mar;64(3):277-278. doi: 10.1165/rcmb.2020-0523ED

Early life microbial exposures and allergy risks: opportunities for prevention

Nat Rev Immunol 2021 Mar;21(3):177-191. doi: 10.1038/s41577-020-00420-y







Current and future treatments of pulmonary arterial hypertension

Br J Pharmacol 2021 Jan;178(1):6-30. doi: 10.1111/bph.15016


Lack of Contribution of p66shc to Pressure Overload-Induced Right Heart Hypertrophy

Int J Mol Sci 2020 Dec 8;21(24):9339. doi: 10.3390/ijms21249339

Asthma-associated risk for COVID-19 development

J Allergy Clin Immunol 2020 Dec;146(6):1295-1301. doi: 10.1016/j.jaci.2020.09.017


Activation of Group 2 Innate Lymphoid Cells via TL1A/DR3. A Solution to Corticosteroid Resistance?

Am J Respir Crit Care Med 2020 Oct 15;202(8):1067-1069. doi: 10.1164/rccm.202007-2658ED

Advanced risk stratification of intermediate risk group in pulmonary arterial hypertension

Pulm Circ 2020 Oct 7;10(4):2045894020961739. doi: 10.1177/2045894020961739

Risk assessment in severe pulmonary hypertension due to interstitial lung disease

J Heart Lung Transplant 2020 Oct;39(10):1118-1125. doi: 10.1016/j.healun.2020.06.014

Evaluation of pulmonary hypertension by right heart catheterisation: does timing matter?

Eur Respir J 2020 Sep 3;56(3):1901892. doi: 10.1183/13993003.01892-2019

Editorial: Early Life Origins of Immune-Mediated Disease

Front Immunol 2020 Sep 3;11:2050. doi: 10.3389/fimmu.2020.02050


Decreased Thymic Output Contributes to Immune Defects in Septic Patients

J Clin Med 2020 Aug 20;9(9):2695. doi: 10.3390/jcm9092695

Ruxolitinib for the treatment of SARS-CoV-2 induced acute respiratory distress syndrome (ARDS)

Leukemia 2020 Aug;34(8):2276-2278. doi: 10.1038/s41375-020-0907-9

Laboratory characteristics of patients infected with the novel SARS-CoV-2 virus

J Infect 2020 Aug;81(2):205-212. doi: 10.1016/j.jinf.2020.06.039

Impact of SARS-CoV-2 pandemic on pulmonary hypertension out-patient clinics in Germany: a multi-centre study

Pulm Circ 2020 Jul 23;10(3):2045894020941682. doi: 10.1177/2045894020941682





NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD

Nat Metab 2020 Jun;2(6):532-546. doi: 10.1038/s42255-020-0215-8



Current and Future Point-of-Care Tests for Emerging and New Respiratory Viruses and Future Perspectives

Front Cell Infect Microbiol 2020 Apr 29;10:181. doi: 10.3389/fcimb.2020.00181


Association of right atrial conduit phase with right ventricular lusitropic function in pulmonary hypertension

Int J Cardiovasc Imaging 2020 Apr;36(4):633-642. doi: 10.1007/s10554-019-01763-x

Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development

Front Immunol 2020 Mar 31;11:513. doi: 10.3389/fimmu.2020.00513

Preschool wheezing diagnosis and management-Survey of physicians' and caregivers' perspective

Pediatr Allergy Immunol 2020 Feb;31(2):206-209. doi: 10.1111/pai.13142



Evaluation and Prognostic Relevance of Right Ventricular-Arterial Coupling in Pulmonary Hypertension

Am J Respir Crit Care Med 2020 Jan 1;201(1):116-119. doi: 10.1164/rccm.201906-1195LE


Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure

J Am Heart Assoc 2019 Nov 5;8(21):e013584. doi: 10.1161/JAHA.119.013584




Riociguat for treatment of pulmonary hypertension in COPD: a translational study

Eur Respir J 2019 Jun 27;53(6):1802445. doi: 10.1183/13993003.02445-2018

Protection against pressure overload-induced right heart failure by uncoupling protein 2 silencing

Cardiovasc Res 2019 Jun 1;115(7):1217-1227. doi: 10.1093/cvr/cvz049

Alternative Oxidase Attenuates Cigarette Smoke-induced Lung Dysfunction and Tissue Damage

Am J Respir Cell Mol Biol 2019 May;60(5):515-522. doi: 10.1165/rcmb.2018-0261OC

Component-Resolved Diagnosis in Allergic Rhinitis and Asthma

J Appl Lab Med 2019 Mar;3(5):883-898. doi: 10.1373/jalm.2018.026526

Molecular diagnosis for allergen immunotherapy

J Allergy Clin Immunol 2019 Mar;143(3):831-843. doi: 10.1016/j.jaci.2018.12.1021

"Molecular extracts" for allergy diagnostics and therapy

Pediatr Allergy Immunol 2019 Feb;30(1):55-58. doi: 10.1111/pai.13001


Reserve of Right Ventricular-Arterial Coupling in the Setting of Chronic Overload

Circ Heart Fail 2019 Jan;12(1):e005512. doi: 10.1161/CIRCHEARTFAILURE.118.005512


Advances in mechanisms of allergic disease in 2017

J Allergy Clin Immunol 2018 Dec;142(6):1730-1739. doi: 10.1016/j.jaci.2018.09.027

Resolvin E1 and its precursor 18R-HEPE restore mitochondrial function in inflammation

Biochim Biophys Acta Mol Cell Biol Lipids 2018 Sep;1863(9):1016-1028. doi: 10.1016/j.bbalip.2018.06.011

Hypoxic pulmonary vasoconstriction in isolated mouse pulmonary arterial vessels

Exp Physiol 2018 Sep;103(9):1185-1191. doi: 10.1113/EP087117

Influenza-derived peptides cross-react with allergens and provide asthma protection

J Allergy Clin Immunol 2018 Sep;142(3):804-814. doi: 10.1016/j.jaci.2017.07.056

Anoctamin-1: A Novel Mitochondrial Ion Channel Regulating Cellular Apoptosis and Proliferation?

Am J Respir Cell Mol Biol 2018 May;58(5):558-559. doi: 10.1165/rcmb.2017-0355ED

Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension

Eur Respir J 2018 Feb 1:1701024. doi: 10.1183/13993003.01024-2017

Vaccination and allergy: EAACI position paper, practical aspects

Pediatr Allergy Immunol 2017 Nov;28(7):628-640. doi: 10.1111/pai.12762

Human Milk and Allergic Diseases: An Unsolved Puzzle

Nutrients 2017 Aug 17;9(8):894. doi: 10.3390/nu9080894

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Circ Res 2017 Aug 4;121(4):424-438. doi: 10.1161/CIRCRESAHA.116.310482

Cellular and noncellular bloodborne biomarkers in asthma

Ann Allergy Asthma Immunol 2017 Jun;118(6):672-679. doi: 10.1016/j.anai.2017.04.016


Performance evaluation of ImmunoCAP® ISAC 112: a multi-site study

Clin Chem Lab Med 2017 Mar 1;55(4):571-577. doi: 10.1515/cclm-2016-0586. PMID: 27816950


Mitochondrien als universelle Sensoren der akuten Hypoxie?

Biospektrum (Heidelb) 2022;28(2):132-134. German. doi: 10.1007/s12268-022-1742-5

Experimental Setup for Investigation of Acute Mitochondrial Oxygen Sensing in Primary Cells

Methods Mol Biol 2022;2497:301-311. doi: 10.1007/978-1-0716-2309-1_20

Assessment of Short- and Medium-Chain Fatty Acids on Mitochondrial Function in Severe Inflammation

Methods Mol Biol 2021;2277:125-132. doi: 10.1007/978-1-0716-1270-5_8



Lung Ischaemia-Reperfusion Injury: The Role of Reactive Oxygen Species

Adv Exp Med Biol 2017;967:195-225. doi: 10.1007/978-3-319-63245-2_12

Principal Investigators

Natascha Sommer

PD Dr. med, PhD Natascha Sommer

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

Chrysanthi Skevaki

Dr. Chrysanthi Skevaki

Philipps-Universität
Marburg Institute of Laboratory Medicine
Baldingerstraße; 35043 Marburg

+49-6421 28-21443

Project group

  • Sara Völkel

    Sara Völkel , Postdoc

  • Thilo Berger

    Thilo Berger , PhD Student

  • Hannah Janocha

    Hannah Janocha , MD student

  • Charlotte Mara Heinrich

    Charlotte Mara Heinrich , Technician