Pyroptosis and Pyroptosis Like: Two stories of Macrophage death against bacterial invaders
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
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