Regulation of Human Cell Death Responses to Yersinia Infection / Neha Mahalakshmi Nataraj.

Format:

Book

Thesis/Dissertation

Author/Creator:

Nataraj, Neha Mahalakshmi, author.

Contributor:

University of Pennsylvania. Immunology, degree granting institution.

Language:

English

Subjects (All):

Immunology.

Microbiology.

Cellular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Local Subjects:

Immunology.

Microbiology.

Cellular biology.

Immunology--Penn dissertations.

Penn dissertations--Immunology.

Physical Description:

1 online resource (118 pages)

Distribution:

Ann Arbor : ProQuest Dissertations & Theses, 2023

Contained In:

Dissertations Abstracts International 85-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Language Note:

English

Summary:

Regulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gram-negative bacterial pathogens in the Yersinia genus disrupt NF-κB signaling via translocated effectors injected by a type III secretion system (T3SS), thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection, Yersinia blockade of NF-κB signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival. However, significant differences in immune genes exist between humans and mice. Using in vitro infection models and CRISPR-Cas9 technology, we sought to uncover how Yersinia-induced cell death signaling works in human macrophages. Unexpectedly, we find that human macrophages undergo apoptosis independently of RIPK1 in response to Yersinia or chemical blockade of IKKβ. Instead, IKK blockade led to decreased cFLIP expression, and overexpression of cFLIP contributed to protection from IKK blockade-induced apoptosis in human macrophages. Importantly, IKK blockade also induces RIPK1 kinase-independent apoptosis in human T cells and human pancreatic cells. Altogether, our data indicate that, in contrast to murine cells, blockade of IKK activity in human cells triggers a distinct apoptosis pathway that is independent of RIPK1. These findings have implications for the contribution of RIPK1 to cell death in humans and the efficacy of RIPK1 inhibition in human diseases.

Notes:

Source: Dissertations Abstracts International, Volume: 85-08, Section: B.

Advisors: Brodsky, Igor E.; Shin, Sunny; Committee members: Henao-Mejia, Jorge; Laufer, Terri M.; Yang, Xiaolu; Bailis, Will.

Department: Immunology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798381510454

Access Restriction:

Restricted for use by site license.