Investigating Cell Type-Specific Responses to Legionella pneumophila Infection Victor R Vazquez Marrero

Format:

Book

Thesis/Dissertation

Author/Creator:

Vazquez Marrero, Victor R., author.

Contributor:

University of Pennsylvania. Immunology., degree granting institution.

Language:

English

Subjects (All):

Immunology.

Microbiology.

Molecular biology.

0982.

0410.

0307.

Local Subjects:

Immunology.

Microbiology.

Molecular biology.

0982.

0410.

0307.

Physical Description:

1 electronic resource (224 pages)

Contained In:

Dissertations Abstracts International 86-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and uses inflammasomes and guard proteins to sense cytosolic PAMPs or pathogen-specific activities, thereby activating effector-triggered immunity (ETI). Cytokine-mediated activation further amplifies these responses and shapes immune cell function. How distinct innate immune cell types integrate PRR-, ETI-, or cytokine-dependent defenses during bacterial infection remains poorly understood. To address this, we investigated innate immune responses to the bacterial pathogen Legionella pneumophila in murine dendritic cells (DCs) and human monocytes. Legionella uses its Dot/Icm type IV secretion system (T4SS) to inject effector proteins that promote robust intracellular replication in macrophages, but in DCs, T4SS activity inadvertently triggers rapid cell death, thereby limiting bacterial replication. Mechanistically, we found heterogeneity in the DC death response at the single-cell level. Early during infection, a subset of DCs activates caspase-11 and NLRP3 inflammasome-dependent pyroptosis. At later stages, a separate DC population undergoes apoptosis driven by T4SS effectors that inhibit host protein synthesis, depleting the pro-survival proteins Mcl-1 and cFLIP. These findings suggest that Mcl-1 and cFLIP act as guards of host protein synthesis in DCs, and that pathogen interference leads to apoptosis. Together, pyroptosis and effector-triggered apoptosis effectively limit Legionella replication in DCs. In addition to investigating DC responses, we explored the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in human monocytes. Our results show that Legionella- and TLR-dependent NF-κB signaling is a prerequisite for GM-CSF-driven cytokine expression. Subsequently, GM-CSF-induced JAK2/STAT5 signaling is required to further amplify cytokine production. Additionally, PI3K/Akt/mTORC1 signaling, along with glycolysis and amino acid metabolism, is critical for GM-CSF-mediated cytokine upregulation. Collectively, this work provides new insights into how different innate immune cell types harness PRR-, ETI-, and cytokine-dependent mechanisms to mount tailored responses against intracellular bacterial infection

Notes:

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Advisors: Shin, Sunny Committee members: Zackular, Joseph; Jurado, Kellie; Brodsky, Igor E.; Hunter, Christopher A.

Ph.D. University of Pennsylvania 2025

Local Notes:

School code: 0175

ISBN:

9798280756427

Access Restriction:

Restricted for use by site license