All ETDs from UAB

Advisory Committee Chair

Janet yother

Advisory Committee Members

William Benjamin

Kevin Dybvig

Susan Hollingshead

Michael Niederweis

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Streptococcus pneumoniae is a versatile organism that adapts to many different environments in the host. S. pneumoniae can asymptomatically colonize the nasopharynx of humans. However, dissemination of the bacterium from the nasopharynx to different locations in the body can lead to invasive diseases such as pneumonia, bacteremia, and meningitis. How S. pneumoniae modulates factors that are important for survival in these niches has not been well characterized. In the studies described here, we propose that S. pneumoniae may modulate gene expression in these niches by sensing the different glu-cose concentrations via carbon catabolite control protein A (CcpA). Initially we characterized CcpA-dependent regulation of bgaA, a surface-associated β–galactosidase, via CcpA’s binding to the promoter of the upstream pts op-eron, one of the main sugar transporters of the cell. The regulation of bgaA by CcpA was altered by changing the sugars in the growth medium. Furthermore, repression of bgaA was shown to increase with increasing glucose concentrations. We also demonstrated that NanA, a neuraminidase, was repressed by CcpA. This repression was alleviated in the absence of glucose. Both BgaA and NanA are differentially regulated in phase variants of S. pneumoniae. S. pneumoniae exhibits two phase variable phenotypes, opaque and trans-parent. Previous studies have shown that transparent variants have increased levels of BgaA, NanA, StrH, and PspC, but decreased capsule production. In contrast, opaque variants have increased capsule production, but decreased levels of BgaA, NanA, StrH, ii and PspC. Differential expression of these phase variable factors leads to increased colo-nization by transparent variants, whereas opaque variants are better adapted for systemic infections. We hypothesized that CcpA may be involved in sensing environmental condi-tions and differentially regulating phase variable factors. We have shown that CcpA responds to the changing metabolic state of the cell due to alterations in available glucose and up-regulates or down-regulates phase variable fac-tors. In the nasopharynx, glucose is undetectable, which leads to decreased metabolism in the cell. CcpA responds to the decreased glucose and up-regulates factors involved in colonization, such as BgaA, NanA, and LytA, and down-regulates capsule. In contrast, in the blood where normal glucose concentrations are 0.1%, the cell is actively metabolizing the sugar leading to CcpA activation of capsule and repression of BgaA, NanA, and LytA. Other regulatory mechanisms besides CcpA are involved in glucose-mediated regulation, as shown by the fact that StrH activity responds to changing glucose concen-trations but was not affected by CcpA. In conclusion, we have characterized a key regula-tory pathway enabling S. pneumoniae adaptation to changing environments.



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