Dissertation Seminar – Kara Eichelberger

Kara Eichelberger

“Yersinia pestis-host cell interactions during distinct inflammatory phases of primary pneumonic plague.”

Friday, November 22, 2019

3:00 p.m.

1131 Bioinformatics

Dissertation Advisor: Dr. Bill Goldman

Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy

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Kara Eichelberger

Abstract

Inhalation of Yersinia pestis causes primary pneumonic plague, one of the deadliest manifestations of plague. The pneumonic form of plague has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Y. pestis pulmonary infections are incompletely understood. Primary pneumonic plague progresses in two distinct phases as defined by host immune responses and disease pathology. Inhaled Y. pestis colonizes the lungs and replicates to high numbers during the initial asymptomatic pre-inflammatory phase. After this time, disease progresses into the pro-inflammatory phase, and Y. pestis can be detected in the bloodstream and other organs. This second phase is characterized by the rapid onset of symptoms, high levels of pro-inflammatory cytokines in the lung, and a massive influx of neutrophils into the alveolar spaces. The goal of the research described in this dissertation was to characterize Y. pestis interactions with host cells and manipulations of the immune response during the different phases of disease. In Chapter 2, I used transposon sequencing to identify genes involved in Y. pestis adherence in the lung early after inoculation. I identified enrichment of genes involved in the regulation and assembly of macromolecules and determined that YPO3903, encoding a hypothetical protein, mediates adherence of Y. pestis wild-type following intranasal inoculation. In Chapter 3, I investigated bacterial burdens and IL-1 cytokine levels as factors initiating the pro-inflammatory switch. High Y. pestis lung burdens, but not bloodstream burdens or the changing ratio of pro- and anti-inflammatory IL-1 cytokines, trigger the onset of inflammation in the lung during primary pneumonic plague. In Chapter 4, I examined the effects of Y. pestis infection on neutrophil degranulation during the pro-inflammatory phase. I determined that Y. pestis inhibits neutrophil exocytosis of primary granules through direct type III secretion system translocation of effectors YopE and YopH. Taken together, these findings demonstrate the ability of Y. pestis to manipulate pulmonary immune defenses and cause severe disease in the lung.

Dissertation Seminar_Eichelberger