Date of Award

Spring 5-6-2022

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Melody N. Neely

Second Committee Member

Melissa Maginnis

Third Committee Member

Sally Molloy

Additional Committee Members

Robert Wheeler

Pauline L. Kamath

Abstract

Bacteria need suitable and resourceful environments to live and reproduce, including soil, oceans, plants, animals and humans. Streptococci are Gram positive pathogens that have the ability to infect a wide variety of hosts including fish, horses, swine, cattle and humans. Among the many streptococcus species, Streptococcus agalactiae (Group B streptococcus or GBS) is an opportunistic pathogen that has been identified as the leading cause of sepsis and meningitis in neonates, in addition to causing invasive and systemic infections in immunocompromised individuals. To survive inside different host environments, bacteria utilize many virulence factors to combat the host immune response, including the bacterial cell wall and capsule. In Gram positive pathogens, the LytR-CpsA-Psr (LCP) family of proteins are vital to the proper synthesis and assembly of both the cell wall and capsule. Three main members of the LCP family proteins have been identified in GBS, including the CpsA, the Psr, and the LytR (BrpA) proteins. This dissertation aimed to examine the effect of the GBS LCP proteins, CpsA and Psr, on vitality of GBS. We showed that both the Psr protein and the CpsA protein play an important role in cell wall integrity, antibiotic sensitivity, and virulence of GBS. The double deletion of genes encoding CpsA and Psr resulted in an exacerbated effect on these processes, alluding to the idea that the two proteins are partially compensatory in function. In addition, work reported in this dissertation aimed to examine the roles of different domains within the CpsA protein in GBS, including the extracellular accessory domain and the highly mobile interdomain region between the accessory and the LytR domains. Results demonstrated that while the absence of the accessory domain and the interdomain region cause the formation of longer cocci chains, it appears to have no significant effect on capsule production in GBS. Overall, the work reported here provides strong evidence that the LCP proteins, in particular CpsA and Psr, play a major role in supporting GBS virulence by providing a strong defense through synthesis of a robust cell envelope. These extracellular proteins provide major targets for development of new antimicrobial strategies.

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