Author ORCID Identifier

https://orcid.org/0000-0002-5813-6109

Date of Award

5-4-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Zehava Eichenbaum

Second Advisor

Kuk-Jeong Chin

Third Advisor

Roberta Attanasio

Abstract

The Group A streptococcus (GAS) produces millions of infections worldwide, leading to acute diseases, post-infection sequelae, and severe complications. This leading human pathogen requires iron for growth and relies on the heme-iron it obtains from host hemoproteins to fulfill its need for the metal during infection. Since heme is a critical nutrient for GAS within the host environment, the proteins involved in heme capture and metabolism could be targeted for the development of new modalities to treat and prevent GAS infections and their devastating complications. The 10-gene sia operon, which consists of two surface receptors (Shr and Shp), and an ABC transporter (SiaABC), is the best-described heme capture and import system in GAS. The function of the remaining siaDEFGH genes is not yet characterized. Mutants in the characterized heme uptake proteins (shr, shp, or siaABC) exhibit reduced ability to grow on heme iron, but the partial phenotype indicates other GAS genes contribute to heme metabolism. This dissertation addresses the knowledge gaps in the current understanding of heme uptake in GAS and investigates the potential of targeting the surface receptor, Shr, for the development of new therapy. The first chapter describes a new surface receptor, HupY, and demonstrates that HupY binds heme in vitro, contributes to iron acquisition from hemoglobin or serum, and GAS colonization of the mucosal surfaces in mice. The second chapter shows that the siaFGH genes encode a new type of heme importer that is vital for GAS growth on hemoglobin iron, colonization of the vaginal surface, and systemic infections in murine models. The third chapter describes high-affinity human monoclonal antibody against the surface receptor Shr, their efficacy in protecting from GAS infection in murine models, and investigate their defense mechanism. Altogether this dissertation significantly expands the current understanding of heme metabolism in GAS and lays the groundwork for the development of new therapeutic measures.

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