A zebrafish model to study the schistosome egg granuloma

Schistosomiasis is a disease caused by parasitic flatworms which reside within the venules of their human host. The disease pathology is caused by the eggs which they produce, and is primarily characterized by the granulomas which form around them. While the granulomas have pathological consequences to the host, they are thought to be essential to facilitate egg expulsion and completion of the parasite life cycle. Here, I have developed a larval zebrafish model to study the formation of the schistosome egg granuloma in detail within an optically transparent animal. I have developed the tools and techniques for implantation of individual Schistosoma mansoni eggs into zebrafish, followed by intravital microscopy to observe the formation of the schistosome egg granuloma. Within the zebrafish, eggs induce the formation of epithelioid granulomas, as in mammalian models. I find that while mature schistosome eggs induced granuloma formation, immature eggs do not, and this is due to their eggshell functioning as an immunologically inert barrier between the parasite and host. Complemented by the finding that only mature eggs are shed in both mice and humans, these findings indicate that immature parasite eggs avoid foreign body granuloma formation to prevent premature expulsion during their host-dependent development. Then, after completing development, the mature egg secretes antigens through its eggshell to promote granuloma formation and expulsion to complete its life cycle. I investigate the host and parasite factors involved in granuloma formation, and demonstrate that TNF receptor 1 signaling is not required for either initial macrophage recruitment or granuloma formation, but does contribute to granuloma enlargement. In contrast, the major egg antigen, omega-1, utilizes its RNase activity to induce initial macrophage recruitment.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Takaki, Kevin

Advisor dc:contributor.advisor

• Ramakrishnan, Lalita

• Schistosomiasis
• Schistosoma
• Granuloma
• Zebrafish

Licence

• https://www.repository.cam.ac.uk/bitstreams/f4b49144-8c87-47d9-8663-65fbc749ce39/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.64656

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/317541