Theses and Dissertations

ORCID

0000-0003-1479-182X

Advisor

Thornton, Justin

Committee Member

Gordon, Donna

Committee Member

Jordan, Heather

Committee Member

Seo, Keun

Date of Degree

8-12-2026

Original embargo terms

Embargo 1 year

Document Type

Dissertation - Open Access

Major

Biological Sciences

Degree Name

Doctor of Philosophy (Ph.D.)

College

College of Arts and Sciences

Department

Department of Biological Sciences

Abstract

Streptococcus pneumoniae is a leading cause of pneumonia, bacteremia, and meningitis worldwide. Its ability to cause disease depends on successful colonization of the human nasopharynx, which is the essential first step before transmission and invasive disease. While capsular polysaccharide-based vaccines have reduced disease from vaccine serotypes, their effectiveness is limited by serotype specificity, capsule switching, and serotype replacement. These challenges highlight the need for serotype-independent approaches targeting conserved pneumococcal proteins involved in host interactions and colonization. In this dissertation, we investigated the interactions between pneumococcal adhesins and host receptors to identify protein targets and functional epitopes that could be significant for the development of next-generation protein-based vaccines. The studies presented here define a receptor-centered framework for pneumococcal adherence. First, structure-based mapping of pneumococcal surface adhesin A (PsaA) identified its C-terminal subdomain as the primary region interacting with ANXA2. Far-western blotting, cell-binding assays, and flow cytometry confirmed that this domain mediates specific binding to cell-surface annexin A2 (ANXA2). Antibodies against this region significantly reduced both PsaA binding and pneumococcal adherence to epithelial cells. Second, we used recombinant ANXA2 as a probe and found that multiple proteins in lysates of the TIGR4-derived unencapsulated strain JS1 interact with this host receptor. This finding supports the idea that pneumococci might use ANXA2 as a shared epithelial binding platform, rather than relying on a single ligand. Third, we compared receptor profiles of six choline-binding proteins (CBPs): PcpA, CbpE, CbpG, CbpJ, CbpL, and CbpM using A549 and Detroit 562 epithelial lysates. This analysis revealed distinct host-binding patterns and showed that several CBPs preferentially recognize trypsin-sensitive, surface-accessible host targets. The combination of these studies demonstrates that pneumococcal colonization relies on a network of conserved adhesin-host interactions, including both shared receptor usage and domain-specific adhesin recognition. This work advances our understanding of pneumococcal adherence and provides a framework for developing multicomponent, protein-based vaccines to block colonization and provide broad protection across pneumococcal serotypes.

Sponsorship (Optional)

R15AI142537 (JAT)

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