Universität zu Köln

Hos, Nina Judith (2019). The Role of Type I Interferon in Regulating Macrophage Responses to Salmonella Typhimurium Infection. PhD thesis, Universität zu Köln.

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Abstract

Salmonella Typhimurium (S. Typhimurium) is a Gram-negative, facultative intracellular bacterium that exploits the host’s type I interferon (IFN-I) response to induce cell death in macrophages. We have previously demonstrated that activation of the IFN-I receptor (Ifnar1) results in recruitment of RIP1 and subsequent formation of a RIP1/RIP3 complex, leading to a specific form of programmed cell death, termed necroptosis, in S. Typhimurium-infected macrophages (Robinson et al. 2012). Despite our detailed knowledge on IFN-I/RIP1/RIP3-dependent necroptosis execution, the IFN-I-mediated pathways that determine whether infected macrophages will undergo necroptosis remain elusive. This work therefore sought to identify the IFN-I-mediated events that sensitize S. Typhimurium-infected macrophages to cell death. Here, we demonstrate that S. Typhimurium infection causes mitochondrial damage and impairs the host´s anti-oxidative stress response through upregulation of the mitochondrial phosphatase Pgam5 downstream of IFN-I/RIP3. Pgam5 subsequently interacts with the transcription factor Nrf2, which sequesters Nrf2 in the cytosol thereby repressing the transcription of Nrf2-dependent anti-oxidative genes. The impaired ability to respond to S. Typhimurium-induced oxidative stress results in ROS-mediated mitochondrial damage, ATP depletion, transient induction of autophagy, and autophagy-mediated degradation of p62, which impairs p62-Keap1 interaction. Consequently, Keap1 interacts more with Nrf2, which further represses Nrf2 function and additionally impairs anti-oxidative stress responses to S. Typhimurium infection thereby sensitizing macrophages to cell death. Taken together, we identify impaired Nrf2-dependent redox homeostasis of S. Typhimurium-infected macrophages as an important mechanism that drives cell death downstream of IFN-I/RIP3.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Hos, Nina Judith nina.hos@uk-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-97227
Date:	21 May 2019
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Medicine > Medizinische Mikrobiologie, Immunologie und Hygiene > Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Macrophage English Salmonella English Type I interferon English anti-oxidative response English cell death English
Date of oral exam:	21 May 2019
Referee:	Name Academic Title Höning, Stefan Prof. Dr. Antebi, Adam Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/9722