Theses and Dissertations

ORCID

https://orcid.org/0000-0002-1011-4744

Advisor

Abdelhamed, Hossam

Committee Member

Lawrence, Mark

Committee Member

Pruett, Stephen

Committee Member

Nanduri, Bindu

Date of Degree

5-16-2025

Original embargo terms

Visible MSU Only 2 Years

Document Type

Dissertation - Campus Access Only

Major

Veterinary and Biomedical Sciences (Infectious Diseases)

Degree Name

Doctor of Philosophy (Ph.D.)

College

College of Veterinary Medicine

Department

Department of Comparative Biomedical Sciences

Abstract

Listeria monocytogenes is a facultative intracellular pathogen responsible for listeriosis, a severe disease in humans and animals. The bacterium's ability to survive and transition between environmental and host conditions is governed by a complex network of transcriptional regulators. This dissertation investigates the roles of LysR-type transcriptional regulators (LTTRs), including catabolite control protein C (CcpC) and glutamate synthase gene (GltC) and uncharacterized LTTRs in L. monocytogenes physiology, metabolic adaptation, virulence, and stress responses. Deletion of ccpC resulted in impaired phospholipase activity, reduced expression of the cholesterol-dependent cytolysin listeriolysin O (LLO), and diminished bacterial burden in murine liver and spleen. Transcriptomic analysis revealed that ccpC deletion led to the upregulation of DNA repair, stress response, and peptidoglycan biosynthesis genes while downregulating virulence and metabolic genes. Metabolomic profiling further demonstrated shifts in intracellular metabolites, indicating a significant role for ccpC in regulating nitrogen metabolism and bacterial competitiveness. In contrast, the deletion of gltC has a limited impact on phospholipase activity and cell-to-cell spread and intracellular replication. Furthermore, gltC deletion increased bacterial survival under oxidative stress and enhanced virulence in a murine model, suggesting that gltC may function as a negative regulator of virulence genes. Transcriptomic analysis of the gltC mutant revealed significant upregulation of genes involved in virulence, nitrogen metabolism, and oxidative stress response. Additionally, this study examined six uncharacterized LTTRs (LMOf2365_2178, LMOf2365_2322, LMOf2365_2266, LMOf2365_0315(315), LMOf2365_0518(518), and LMOf2365_0446 (446), demonstrating their involvement in phospholipase activity, LLO expression, and PrfA-mediated virulence regulation. Collectively, these findings highlight the crucial roles of LTTRs in modulating L. monocytogenes metabolism, virulence, and stress adaptation. Understanding these regulatory networks enhances our knowledge of L. monocytogenes pathophysiology and may inform the development of targeted interventions to mitigate its pathogenicity.

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