Date of Award

5-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Computer Science

First Advisor

Kourosh Zarringhalam

Second Advisor

Marc-Jan Gubbels

Third Advisor

Nurit Haspel

Abstract

Toxoplasma gondii is a member of the phylum Apicomplexa, which comprises many obligate intracellular parasites, including the malaria-causing Plasmodium spp. T. gondii causes opportunistic infections in humans. The global prevalence has been estimated to be between 30 – 50 % [1]. T. gondii infection consists of a short acute phase, caused by the tachyzoite stage, and a life-long chronic phase maintained by the bradyzoite stage [2]. Most infected individuals are asymptomatic; however, infection can lead to severe clinical disease including ocular lesions and neurological disorders in immunocompromised patients or in the case of congenital transmission to the developing fetus [3]. Disease pathogenesis is primarily the result of the repeated rounds of lytic cycle, causing uncontrolled expansion of parasite biomass, the associated tissue destruction, and ensuing inflammation [4]. T. gondii’s lytic cycle comprises of an asexual cell division cycle known as endodyogeny followed by egress from the host cell and reinvasion of a new host [5]. Increased efficiency in steps of the lytic cycle, including reinvasion, replication rate, and extracellular survival, can result in enhanced virulence.

In this dissertation, we have developed analytical approaches to analyze high-dimensional gene expression and chromatin accessibility datasets to study the fundamental processes and genetic factors underlying asexual reproduction and the regulation of virulence in T. gondii. We present time-series clustering methodologies for identifying gene classes, network reconstruction techniques to identify co-expressed genes, and novel pseudo-time analysis methods to map the developmental trajectory of replicating parasites. Our results indicate that transcriptional regulation plays a major role in enhanced virulence and that modules of co-regulated genes drive the cell division cycle. Overall, the work presented in this thesis provides a tailored toolbox of computational models for analysis of cell replication in T. gondii. These tools are general and can be adapted to study other apicomplexan parasites.

Comments

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