Author ORCID Identifier

https://orcid.org/0000-0002-7045-6594

Semester

Spring

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Biology

Committee Chair

Timothy Driscoll

Committee Member

Mariette Barbier

Committee Member

Jen Gallagher

Committee Member

Joe Gillespie

Committee Member

Rita Rio

Abstract

Vector-borne diseases have been increasing over the past few years due to changes in climate and disturbances in the vectors’ natural environment. To mitigate the risks of these diseases, it is necessary to understand pathogen biology and how it interacts with a host to cause disease. Here we focus our attention on the tick-borne pathogen, Rickettsia rickettsii. R. rickettsii is a member of the spotted fever group (SFG) Rickettsiae and is the etiological agent of Rocky Mountain spotted fever (RMSF), a fatal human disease that is lacking an effective vaccine. Members of the bacterial genus Rickettsia are obligate intracellular endoparasites that have been shown to infect a variety of eukaryotic cell types. Although certain rickettsial surface proteins have been characterized in some detail, the combination of proteins used during entry and infection of different host cell types is not clear. In this work, we compare R. rickettsii with Rickettsia montanensis, a much less pathogenic species with very high genomic similarity. The basis for this substantial difference in phenotype from two highly similar genotypes is not known; consequently, we have used these two species to 1) identify transcripts that may be related to R. rickettsii’s ability to cause disease in a human host and its ability to infect various host cell types; and 2) compare the host cellular response to these two rickettsiae. I begin this dissertation by discussing the current knowledge in the field pertaining to rickettsial entry and survival within host cells. I then show the potential role of host extracellular vesicles formation, cytokine signaling, and epigenetic remodeling during SFG rickettsial infections in infected spleen tissue. I also describe different transcriptional responses in infected liver tissue, highlighting that rickettsiae interact with host cells differently dependent on tissue type and perhaps host cell type. I follow up this in vivo work with culture experiments, showings that 1) R. rickettsii and R. montanensis elicit different endothelial cell responses during infection and 2) the two species express a different profile of transcripts during infection of endothelial cell and differentiated THP-1 macrophages. Finally, I show that R. rickettsii and R. montanensis share a nearly identical genome, suggesting the differences in virulence need to be analyzed on a multi- omics level. Taken together, the results of my dissertation highlight a potential link between differential gene/protein expression and differences in virulence between rickettsial species. This suggests that multi-omics analyses will prove very useful in determining the cause of differences in virulence between rickettsial species and how rickettsiae interact with different host organisms and cell types.

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