Universität zu Köln

Gluschko, Alexander ORCID: 0000-0002-1090-1756 (2018). LC3-associated Phagocytosis induced by the ß2 integrin Mac-1 enhances Immunity to Infection with Listeria monocytogenes. PhD thesis, Universität zu Köln.

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Abstract

Listeria monocytogenes (L.m.) are targeted by the autophagic machinery, however, the molecular mechanisms involved and the functional consequences for anti-listerial immunity remained unknown. Here, we use an in vivo mouse infection model to show that L.m. infection of tissue macrophages evokes LC3-associated phagocytosis (LAP), but not canonical autophagy, and that targeting of L.m. by LAP is required for anti-listerial immunity. Furthermore, by employing a group of genetically deficient mouse lines, we delineate the molecular pathway leading to induction of LAP in response to L.m. infection and the mechanisms underlying the anti-listerial function of LAP. Induction of LAP in response to L.m. infection is not initiated by TLR2 or MyD88 dependent signaling pathways, but by the ß2 integrin Mac-1 (CR3, integrin αMß2). Interaction of L.m. with Mac-1 results in activation of acid sphingomyelinase, which is essentially required for assembly and activation of the phagocyte NADPH oxidase Nox2. Subsequent production of reactive oxygen species by Nox2 triggers LC3 recruitment to L.m.- containing phagosomes. LC3-positive L.m.-containing phagosomes fuse with lysosomes, which increases exposure of L.m. to bactericidal acid hydrolases and thereby enhances anti-listerial activity of macrophages and immunity of mice.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Gluschko, Alexander alexander.gluschko@uni-koeln.de orcid.org/0000-0002-1090-1756 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-84960
Date:	2018
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language LC3-associated phagocytosis; Listeria monocytogenes; Mac-1/CR3; NAPDH oxidase Nox2; ROS; acid sphingomyelinase; lysosome; macrophages; non-canonical autophagy; β(2) integrin English
Date of oral exam:	20 June 2018
Referee:	Name Academic Title Hoppe, Thorsten Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/8496