Date of Award

2018

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

Abstract

Staphylococcus aureus is a gram-positive, extracellular bacterium that has emerged as an

important human pathogen. This bacterium is a leading cause of skin and soft tissue infections

(SSTIs) in humans, often leading to invasive and life-threatening infections. Treatment of S.

aureus infections is becoming more complicated due to the rise of methicillin-resistant S. aureus

(MRSA) strains, which are becoming increasingly resistant to a number of antibiotics. In the

United States, invasive MRSA infections result in more deaths annually than any other infectious

agent.

Despite a dire need, there is currently no vaccine against S. aureus infections. The failure

of past vaccine candidates may be due to a lack of understanding of immune correlates of

protection and how to obtain them through vaccination. Additionally, attempts to develop

vaccines have, up to this point, focused solely on eliciting high titer antibody responses to

antigens. Accumulating evidence from human patients and in vivo studies suggest that CD4+ T

cells are important mediators of protection from S. aureus infections.

TH17 cells, and their namesake cytokine IL-17, are involved in protection against

cutaneous infections. TH17 cells and IL-17 are important for neutrophil recruitment to sites of

infection, which is required for clearance of S. aureus, as well as antimicrobial peptide (AMP)

production from epithelial cells. Therefore, a protective vaccine will likely require a strong TH17

response to S. aureus antigen. Data also implicates TH1 cells and the associated cytokine IFN? as

important mediators of protection against S. aureus, especially during invasive infection. Based

on these data, the most effective vaccine will likely be one that can elicit strong TH17 and TH1

responses against vaccine antigens.

My goal was to develop an adenovirus (Ad) vector based vaccine that could provide

protection from cutaneous MRSA infections. Ad is an attractive vaccine vector due to its potent

T cell adjuvant capabilities and high level and duration of transgene expression. As T cells have

been shown to be important for immunity to S. aureus, I hypothesized that Ad vectors expressing

domains from MRSA surface proteins as transgenes would elicit more potent T cell responses to

these antigens than protein immunization and would provide protection from cutaneous

infection. I generated Ad vectors expressing MRSA antigens and assessed the immune response

induced by vaccination. I also assessed the ability of these Ad vectors to provide protection

against MRSA infection using a mouse model of cutaneous infection.

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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