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Doctoral thesis
English

Role of cGMP/calcium/lipid signaling related factors in Toxoplasma gondii tachyzoite proliferation and bradyzoite persistence

ContributorsYe, Shu
Number of pages156
Imprimatur date2023
Defense date2023
Abstract

Toxoplasma gondii is a widespread parasite that belongs to the Apicomplexa phylum which also includes Plasmodium species responsible for malaria, and Cryptosporidium spp. causing severe diarrhea in children. T.gondii utilizes different strategies to ensure its rapid propagation during acute infection and long-term persistence during chronic infection. Acute infection is a result of tachyzoite lytic cycles which consist of invasion, replication and exit from host cells. In response to intrinsic or environmental cues, tachyzoites initiate cGMP/calcium/lipid mediated signaling pathways to coordinate microneme secretion and actomyosin-based motility, which ensures tachyzoite egress and invasion. Chronic infection is established by tachyzoites conversion to bradyzoites to form tissue cysts. Bradyzoites replicate asynchronously at a slow speed within cysts. Cyst rupture and bradyzoite invasion lead to cyst dissemination. However, the molecular mechanism of cyst dissemination remains unknown, and no therapy is available to eradicate tissue cysts during chronic infection.

In this thesis, I investigated the role of several factors positioned differently in the cGMP/calcium/lipid mediated signaling pathways for tachyzoite proliferation, cyst dissemination and bradyzoite persistence. A signaling linking factor (SLF) is a new component of the guanylate cyclase (GC) complex which perceives and initiates the cGMP signaling. SLF is critical for GC complex assembly and GC activity. While SLF and GC contribute moderately to the establishment of chronic infection, SLF but not GC is crucial for the natural oral infection with bradyzoite cysts. Diacylglycerol kinase 1(DGK1) is a key mediator that maintains the balance between two lipid secondary messengers (diacylglycerol and phosphatidic acid). The role of DGK1 for microneme secretion and tachyzoite egress was studied previously. Importantly, DGK1 was found to be indispensable for intracellular development of tachyzoites by preserving plasma membrane homeostasis. In my study, DGK1 kinase activity was identified to be critical for its function which is conserved in Plasmodium. DGK1 may be dispensable for bradyzoite persistence. Finally, glideosome-associated connector (GAC) is a key downstream player in response to the cGMP/calcium/lipid signaling. GAC links apico-basal actin flux and secreted microneme adhesins for parasite gliding motility. A bradyzoite-specific knockdown of GAC was generated by replacing the endogenous GAC promoter to tachyzoite specific SAG1 promoter. Interestingly, no tissue cysts formed by GAC promoter swap parasites were detected during the early chronic infection.

The work presented in this thesis revealed that cyst dissemination contributes to cyst burden during chronic infection, and it was found that bradyzoites rely on actomyosin-based motility rather than the GC complex for their dissemination. This finding helps us to understand the mechanism behind cyst dissemination.

eng
Keywords
  • Toxoplasma gondii
  • Chronic infection
  • Tissue cyst
  • Bradyzoite
  • Signaling
  • Invasion
  • Egress
  • Motility
Citation (ISO format)
YE, Shu. Role of cGMP/calcium/lipid signaling related factors in <i>Toxoplasma gondii </i>tachyzoite proliferation and bradyzoite persistence. 2023. doi: 10.13097/archive-ouverte/unige:173052
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Creation11/06/2023 2:13:39 PM
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