Flage, Bethany
(2023)
The role and mechanism of hemoglobin variation in Plasmodium falciparum sexual differentiation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The debilitating effects of human infection by the malaria-causing pathogen Plasmodium falciparum is believed to be the driving force behind the emergence of several different mutations of the hemoglobin (Hb) protein. Today, this group of disorders is the most common monogenic disorder within the human population, and unsurprisingly the most affected populations are those that have, and continue to be, most affected by malaria disease. Together, these two diseases incur a significant public and global health burden. While several variants of Hb provide protection against malaria, this protection is not sterile, and malaria prevalence has been shown to vary based on the prevalence of Hb variant- carriage within certain populations. The relationship between Hb variation and malaria is further complicated by recent epidemiological findings which have found Hb variation may promote the transmission of malaria from human host to mosquito vector. The host to vector transmission of P. falciparum is reliant on the formation of gametocytes, which arise from asexually replicating parasites during the intraerythrocytic stage of human infection. Defining specific factors that promote the formation of transmissible gametocytes from the disease-causing asexual stages has been an area of increased research, as targeting these stages may prevent transmission entirely. Here, we analyze the relationship between the most common Hb variant, Hb S, and the rate of gametocyte conversion in P. falciparum. We find gametocyte conversion rates (GCRs) are significantly increased among erythrocytes expressing Hb S compared to those expressing Hb A. We then find parasitic enzyme-mediated digestion of Hb S occurs more rapidly than Hb A, suggesting an increased release of heme groups carried by each Hb subunit. Then, upon manipulating both intracellular and extracellular hemin concentrations, we found gametocyte conversion to significantly increase. Therefore, we conclude that heme is a causative factor for gametocyte conversion. As levels of both intracellular and extracellular heme are increased in individuals with Hb variants, we propose heme to be a contributing factor for increased gametocyte conversion observed among these populations. These results support further investigation into how heme concentrations may be directly manipulated to prevent commitment to gametocyte formation and ultimately disease transmission.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
9 May 2023 |
| Date Type: |
Publication |
| Defense Date: |
19 April 2023 |
| Approval Date: |
9 May 2023 |
| Submission Date: |
26 April 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
206 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Plasmodium falciparum, sexual differentiation, sexual conversion, heme, hemin, transmission |
| Date Deposited: |
10 May 2023 01:50 |
| Last Modified: |
10 May 2023 01:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44739 |
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