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

Eric Gilbert

Fourth Advisor

Jorge Vidal

Abstract

Streptococcus pneumoniae is a principal human pathogen that colonizes the human nasopharynx and causes a variety of diseases ranging from common infections to life-threatening conditions such as pneumonia, meningitis, and sepsis. During infection, free iron is not available, and thus, invading microbes, such as S. pneumoniae, compete with the host for the metal. The heme-iron bound to hemoglobin is the most abounded form of iron in the human body. S. pneumoniae can obtain iron from hemoglobin, but the bacterial mechanisms involved in this process are only partially described. This dissertation investigated the role of hemoglobin in pneumococcal physiology and virulence. The studies discovered that hemoglobin promotes vigorous S. pneumoniae growth. The pneumococcal growth response is hemoglobin dependent, conserved among pneumococcal serotypes, and not seen with free heme or iron. Hemoglobin also induces an extensive transcriptome remodeling, effecting virulence factors and metabolism, and in particular genes that facilitate the use of host glycoconjugates as a sugar source. The second significant finding of this study is the discovery that hemoglobin promotes robust and early pneumococcal biofilms. The biofilm response is hemoglobin specific, and free iron, heme, or other heme sources such as myoglobin and serum do not induce the response. The addition of human blood also triggers biofilms but required the pneumococcal hemolysin, Ply. S. pneumoniae cells shifting from planktonic growth to biofilms in the presence of hemoglobin exhibit a significant transcriptome shift that includes heme uptake and regulatory systems. The biofilm response to hemoglobin involves the CiaRH two-component system, and the Competence Stimulating Peptide, CSP-1. The data shows that CSP-1 functions in a new mechanism that is independent of its cognate two-component system ComDE. In summary, this dissertation describes a novel role for the host hemoglobin in pneumococcal physiology and pathogenesis. It discusses how these findings advance the current understanding of S. pneumoniae interactions with its obligate human host.

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