ORCID ID

0000-0003-1278-5901

Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Paul D. Fey

Abstract

Staphylococcus aureus is a leading cause of opportunistic infections in community and health care settings. To thrive in a great variety of environments, S. aureus has developed the capability of tolerating temporary pH changes, as well as resisting constant acid stress. To evaluate the impact of strong and weak acid stress on S. aureus, growth patterns of JE2 were monitored when cultured in chemically defined media (CDM) at various pH in the presence of hydrochloric acid (HCl), acetic acid, and lactic acid. Our results showed that S. aureus responds to strong and weak acids in different manners. S. aureus is more susceptible to acetic acid than HCl and is able to alleviate lactate acid stress by consuming lactate. In-depth investigations of lactate catabolism revealed that lactate quinone oxidoreductase (Lqo), and lactate dehydrogenases (Ldh1 and Ldh2) are crucial for lactic acid resistance. In addition, we explored the in vitro and in vivo functions of urease in S. aureus with approaches such as genetic manipulations, growth assays, as well as mouse model systems. We discovered that in contrast to Staphylococcus epidermidis, S. aureus primarily employs the urease pathway to rescue survival under acid stress. Examination of urease regulation indicated that the regulation network is mainly comprised of CcpA, agr, and CodY, suggesting that urease transcription responds to metabolic changes and is tied closely to virulence. Our data demonstrated that urease is essential for S. aureus to resist clearance by host immunity and to persist in the mouse kidneys, underscoring the potential role of urease as a critical virulence factor required for renal infection with S. aureus. Collectively, in these studies we have identified and characterized important systems S. aureus employs when adapting to unfavorable acidic niches, and this knowledge lays the foundation for broadening our understanding of acid resistance mechanisms of S. aureus.

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