Pyroptosis and Pyroptosis Like: Two stories of Macrophage death against bacterial invaders
Liu, Beiyun.
2018
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Abstract: The re-discovery of caspase-11 led to the refinement of the
functions of both caspase-11 and caspase-1. The current consensus is that caspase-11 is
both the initiator and executioner caspase for cell death upon binding by bacterial
lipopolysaccharide present in the cytosol. Caspase-1, on the other hand, is the executioner
caspase for cleavage and activation of various IL-1 family of ... read morecytokines. The actions of
both caspases complete the host defense mechanism of pyroptosis, defined as a necrotic cell
death process with concomitant release of mature IL-1 cytokines. Upstream and downstream
players in the caspase-11 cascade have also been elucidated in rapid succession. The
activation of caspase-11 upon Gram-negative bacterial infection require a family of
proteins known as the Guanylate Binding Proteins (GBPs). Downstream of caspase-11, the pore
forming protein GasderminD (GsdmD) oligomerizes to form plasma membrane pores, resulting in
cell death. Detailed in this dissertation are two projects that I investigated on
macrophage pyroptosis against two different bacterial pathogens. In the first project, I
built upon existing knowledge of GBPs to refine their role and placement in the initiation
of cytosolic pathogen sensing. Here, I used a mutant of Legionella pneumophila that shows
inadvertent cytosol permeability to model the initial response of a naïve macrophage to
cytosol bacterial presence. I report that low levels of GBP expression are maintained by
quiescent Interferon signaling, and is crucial for the timely release of bacterial contents
to initiate downstream immune responses. In the second project, I explored the morphology
of a rapid, necrotic cell death phenotype mediated by caspase-8 during Yersinia species
infection. Using Y. pseudotuberculosis in conjunction with a small molecule inhibitor to
mimic the virulence factor YopJ, I found that caspase-8 activation induced the cleavage of
multiple gasdermins, resulting in a pyroptotic-like cell death morphology and IL-1 release.
I am glad to have been able to first amend and then to add to our understanding of this
rapidly evolving field of host defense known as pyroptosis.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Immunology.
Advisors: Ralph Isberg, and Alexander Poltorak.
Committee: Stephen Bunnell, Brigitte Huber, Debra Poutsiaka, and Joan Mecsas.
Keywords: Immunology, and Cellular biology.read less - ID:
- nc581017c
- Component ID:
- tufts:25429
- To Cite:
- DCA Citation Guide EndNote
