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Elizabeth Liu Dissertation Pathology Department .pdf (13.94 MB)
ETD Abstract Container
Abstract Header
The Autophagy Pathway and Toxoplasma gondii Infection
Author Info
Liu, Elizabeth
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1428103561
Abstract Details
Year and Degree
2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
Abstract
Toxoplasma gondii is an intracellular protozoan that resides in a parasitophorous vacuole within infected host cells. This vacuole shields the parasite from lysosomal degradation. Our laboratory demonstrated that autophagy re-routes this vacuole to the lysosomal compartment causing parasite killing. Autophagy consists in the formation of a double membrane structure called the autophagosome, which sequesters cytoplasmic cargo and leads to fusion with lysosomes for degradation of the contents. In addition to pathogen degradation, autophagy appears to stimulate presentation of microbial antigens. Little is known on whether autophagy (Atg) proteins in antigen presenting cells have differential roles in promoting T cell responses against microbial antigens. Studies here therefore, examined the role of Atg5 and Atg7 in dendritic cells in the production of IL-2 and IFN-¿ by T. gondii-reactive CD4+T cells. We report that deficiency of Atg5 in dendritic cells impairs production of IL-2 and IFN-¿ by T. gondii-reactive CD4+T cells. Atg5 deficiency did not affect expression of CD40, CD80, CD86 or MHC Class II on dendritic cells or their production of IL-12 p70, IL-1ß and TNF-a. This work reveals that it is unlikely that canonical autophagy mediates the role of Atg5 in modulation of cytokine production, since the deficiency of Atg7 did not have appreciable affects on the secretion of IL-2 and IFN-¿ by T. gondii-reactive CD4+T cells. Thus, our work indicates that Atg proteins in dendritic cells can have distinct effects on cytokine production by CD4+T cells. Our laboratory previously reported that CD40-stimulated autophagy is critical for protection against T. gondii. Herein, we explored molecular mechanisms by which CD40 stimulates autophagy. CD40 ligation in macrophages stimulated autocrine TNF-a production that induced delayed JNK1/2 phosphorylation. JNK activation caused phosphorylation of Bcl-2 at Ser 87 and dissociation of Bcl-2 from the autophagy protein Beclin 1. This latter event is known to activate the autophagic function of Beclin 1. Also, CD40 ligation stimulates autophagy via ULK1. CD40 causes CaMKKß-dependent Thr172 phosphorylation of AMPK, a kinase known to activate ULK1. Moreover, CD40 stimulates autophagy via CaMKKß and AMPK. Further elucidation of the regulation of CD40-stimualted autophagy may lead to novel approaches for the treatment of toxoplasmosis.
Committee
Carlos Subauste (Advisor)
Pages
140 p.
Subject Headings
Immunology
;
Pathology
Keywords
Toxoplasma gondii
;
autophagy
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Citations
Liu, E. (2015).
The Autophagy Pathway and Toxoplasma gondii Infection
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1428103561
APA Style (7th edition)
Liu, Elizabeth.
The Autophagy Pathway and Toxoplasma gondii Infection.
2015. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1428103561.
MLA Style (8th edition)
Liu, Elizabeth. "The Autophagy Pathway and Toxoplasma gondii Infection." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1428103561
Chicago Manual of Style (17th edition)
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Document number:
case1428103561
Download Count:
413
Copyright Info
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.