Universität zu Köln

Gräb, Jessica (2020). Deciphering the role of mitogen-activated protein kinases in host cell death induced by Mycobacterium tuberculosis. PhD thesis, Universität zu Köln.

Preview

PDF PhD Thesis Jessica Graeb.pdf Download (2MB) | Preview

Abstract

The emergence and prevalence of Mycobacterium tuberculosis (Mtb) resistant strains requires the development of alternative therapeutic strategies, such as host-directed therapies (HDT), to treat tuberculosis (TB) infections. These HDT act on the host- response to a pathogen rather than directly on the pathogen itself. A HDT already applied to TB patients are corticosteroids, such as dexamethasone, which are combined with antibiotic treatment in a subset of patients. The exact mechanism of action of corticosteroids in TB remains elusive. Mtb is a highly adapted pathogen that continuously exploits the immune system of the host to ensure its own survival. A major mechanism of pathogenesis in TB is the induction of host cell death. Host cell death leads to the escape of Mtb from the phagocyte and results in dissemination of the disease. However, the exact cell death pathway induced by Mtb as well as the key regulators remain unknown. In-depth understanding of this cell death pathway and the protective mechanism of dexamethasone would provide valuable targets for HDT and may allow for a tailored therapy in patients with extensive tissue necrosis and inflammation. In this thesis, I decipher a novel host cell death pathway triggered by Mtb, which can be inhibited by dexamethasone. Infection of macrophages (Mᴓ) with Mtb induces the phosphorylation of p38 mitogen-activated protein kinase (MAPK). I show that p38 MAPK signaling triggers necrosis rather than apoptosis in Mtb-infected phagocytes. The activation of p38 MAPK promotes the dissociation of hexokinase II (HKII) from mitochondria and allows the opening of the mitochondrial permeability transition pore (mPTP). The opening of the mPTP results in adenosine triphosphate (ATP) depletion and finally in necrosis of the host cell. I can show that dexamethasone inhibits this pathway by activating MAPK phosphatase 1 (MKP-1) to downregulate p38 MAPK activity. Moreover, a direct inhibition of p38 MAPK by the specific p38 MAPK inhibitor doramapimod has similar effects on host cell survival. Since corticosteroids are anti-inflammatory drugs, which among others inhibit tumor necrosis factor (TNF) signaling, I further characterized TNF and necroptosis in Mtb-infected cells using mixed lineage kinase domain-like pseudokinase (MLKL) and TNF receptor 1 (TNFR1) knockout Mᴓ. I could demonstrate that the underlying mechanism of dexamethasone is independent from TNF and necroptosis. Thus, my results link p38 MAPK inhibition by corticosteroids or p38 MAPK inhibitors to the abrogation of mitochondria-mediated host cell death in TB infection and provides new opportunities for research on novel HDT concepts.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Gräb, Jessica jessica.graeb@uk-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-117011
Date:	10 August 2020
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Tuberculosis, cell death, innate immunity English
Date of oral exam:	23 June 2020
Referee:	Name Academic Title Kashkar, Hamid Prof. Dr. Schnetz, Karin Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/11701