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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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)
CreatorsEmailORCIDORCID Put Code
Hos, Nina Judithnina.hos@uk-koeln.deUNSPECIFIEDUNSPECIFIED
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:
Type I interferonEnglish
anti-oxidative responseEnglish
cell deathEnglish
Date of oral exam: 21 May 2019
NameAcademic Title
Höning, StefanProf. Dr.
Antebi, AdamProf. Dr.
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/9722


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