Date Available

4-14-2018

Year of Publication

2018

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Microbiology, Immunology, and Molecular Genetics

First Advisor

Dr. Sarah E. F. D'Orazio

Abstract

As a foodborne pathogen, Listeria monocytogenes (Lm) encounters many barriers to invasion and dissemination in the host that may change the nature of host response. Lm has been most commonly studied using intravenous (i.v.) inoculation, however, a method that delivers a bolus of bacteria directly to the bloodstream. Thus, little is known about what systemic and local mediators are triggered during the natural course of infection and how these may impact susceptibility. Our laboratory used foodborne transmission of Lm in mice to assess whether the method of transmission and the specific organ microenvironment could affect infection-induced secretion of type I interferon or prostaglandin E2. Type I interferon is a pro-inflammatory effector secreted in response to viruses that has been proposed to paradoxically down-regulate innate immunity to intracellular bacteria. In contrast to i.v. infection, type I interferon was not detrimental to the immune response when Lm were acquired orally. In fact, most of the anti-inflammatory effects of type I interferon in the spleen were attributable to i.v. but not foodborne infection. Importantly however, downregulation of the receptor for interferon gamma (IFNGR1), previously ascribed to the type I interferon response, was found to be a consequence of infection and unrelated to type I interferon. In the liver, robust recruitment and activation of neutrophils (PMN) is thought to be required for initiation of Lm immunity. Prostaglandin E2 (PGE2) is a lipid mediator most commonly associated with pain and fever that has also been demonstrated to have anti-inflammatory or tolerogenic effects. It is unknown, however, whether foodborne infection induces PGE2 in the liver and if PGE2 then down-regulates PMN activities. Recruitment of PMN to the liver following foodborne infection was robust in both susceptible and resistant animals. Bone marrow PMN from each killed Lm ex vivo with similar efficiency, thus suggesting that if PMN were dysfunctional during the course of natural infection, they were responding to cues in the microenvironment. Accordingly, significantly more PGE2 was made ex vivo by cells from the livers of susceptible animals than from resistant animals. When PGE2 was applied to naïve PMN prior to exposure to Lm, it consistently dampened the killing efficiency of these cells, suggesting that this lipid better known for its pro-inflammatory roles might have anti-inflammatory effects during Lm infection. Overall, these studies indicate that mediators produced as a result of infection may have very different roles dependent on route of inoculation, timing, and the specific organ examined.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2018.127

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