{"id":{"repo_id":"oxford-brookes","oai_identifier":"tle:a05a2762-07ca-4ba0-88ea-c3a6d479f2a0:d6bd9758-527a-46cd-bfe2-c433766e8fca:1"},"canonical_url":"https://search.dev.ndltd.org/etd/oxford-brookes/tle:a05a2762-07ca-4ba0-88ea-c3a6d479f2a0:d6bd9758-527a-46cd-bfe2-c433766e8fca:1","repository":{"repo_id":"oxford-brookes","name":"Oxford Brookes University","base_url":"https://radar.brookes.ac.uk/radar/oai"},"display":{"title":"Unravelling the molecular mechanisms of Leishmania mexicana adhesion in the sand fly vector","abstract":"Adhesion to surfaces is a common strategy employed, especially by pathogens. In Leishmania, adhesion to the sand fly stomodeal valve is critical for infection maintenance and efficient transmission and occurs through its flagellum via a complex adhesion plaque from which filaments in the modified flagellum extend towards the cell body and likely connect to the flagellum attachment zone (FAZ), a cytoskeletal structure important for cell morphogenesis. While three essential kinetoplastid-insect adhesion proteins (KIAPs) are known, the overall proteome of the adhesion complex is obscure. Moreover, the contribution of the FAZ in adhesion and its relationship with the KIAPs remains unclear. Furthermore, in the motile Leishmania form, Myo21 is an important contributor to diverse functions, including cell morphogenesis and flagellar pocket functions. However, its roles in adhesion are unknown. Here, 17 novel adhesion plaque components that localised to the adhered flagellum were identified, including multiple members of the Adhesion Related NTPase-like Domain (ARND) family, conserved across kinetoplastids, of which the canonical member is the newly discovered KIAP4. Deletion of KIAP4 severely impaired haptomonad adhesion, with the mutant parasites unable to colonise the sand fly stomodeal valve. Deletion of FAZ2, FAZ5, and FAZ34 impaired parasite adhesion in vitro. FAZ34 deletion separated the newly identified and distinct set of KIAP2-containing extra-axonemal flagellar filaments from the anterior cell tip, resulting in haptomonad cell bodies that were positioned further from the adhesion plaque, and reduced KIAP1 and KIAP3 levels in the plaque, while the loss of the filaments through KIAP2 deletion resulted in the loss of adhesion. Moreover, Myo21 was identified as an additional component of the KIAP2-containing filaments and was essential for their organisation and integration into the adhered flagellum. Disrupting the organisation of the filaments through Myo21 deletion impaired Leishmania adhesion progression and maturation in vitro. Overall, this thesis establishes that stable haptomonad adhesion is mediated not by a single adhesive structure but by two mechanistically distinct yet functionally integrated modules: (i) a KIAP1/KIAP3/KIAP4-containing adhesion plaque positioned adjacent to the adhesion surface and (ii) a newly defined KIAP2 and Myo21-containing filament system that links the plaque to the anterior cell tip via the flagellum attachment zone (FAZ), with the connection of the latter module to the FAZ being required for the efficient integration of KIAP1 and KIAP3 into the adhesion plaque and stable Leishmania adhesion. Furthermore, this work defines the molecular architecture required for vector colonisation and identifies essential structural elements that may serve as targets for transmission-blocking interventions across kinetoplastid parasites.","abstract_html":"Adhesion to surfaces is a common strategy employed, especially by pathogens. In Leishmania, adhesion to the sand fly stomodeal valve is critical for infection maintenance and efficient transmission and occurs through its flagellum via a complex adhesion plaque from which filaments in the modified flagellum extend towards the cell body and likely connect to the flagellum attachment zone (FAZ), a cytoskeletal structure important for cell morphogenesis. While three essential kinetoplastid-insect adhesion proteins (KIAPs) are known, the overall proteome of the adhesion complex is obscure. Moreover, the contribution of the FAZ in adhesion and its relationship with the KIAPs remains unclear. Furthermore, in the motile Leishmania form, Myo21 is an important contributor to diverse functions, including cell morphogenesis and flagellar pocket functions. However, its roles in adhesion are unknown. Here, 17 novel adhesion plaque components that localised to the adhered flagellum were identified, including multiple members of the Adhesion Related NTPase-like Domain (ARND) family, conserved across kinetoplastids, of which the canonical member is the newly discovered KIAP4. Deletion of KIAP4 severely impaired haptomonad adhesion, with the mutant parasites unable to colonise the sand fly stomodeal valve. Deletion of FAZ2, FAZ5, and FAZ34 impaired parasite adhesion in vitro. FAZ34 deletion separated the newly identified and distinct set of KIAP2-containing extra-axonemal flagellar filaments from the anterior cell tip, resulting in haptomonad cell bodies that were positioned further from the adhesion plaque, and reduced KIAP1 and KIAP3 levels in the plaque, while the loss of the filaments through KIAP2 deletion resulted in the loss of adhesion. Moreover, Myo21 was identified as an additional component of the KIAP2-containing filaments and was essential for their organisation and integration into the adhered flagellum. Disrupting the organisation of the filaments through Myo21 deletion impaired Leishmania adhesion progression and maturation in vitro. Overall, this thesis establishes that stable haptomonad adhesion is mediated not by a single adhesive structure but by two mechanistically distinct yet functionally integrated modules: (i) a KIAP1/KIAP3/KIAP4-containing adhesion plaque positioned adjacent to the adhesion surface and (ii) a newly defined KIAP2 and Myo21-containing filament system that links the plaque to the anterior cell tip via the flagellum attachment zone (FAZ), with the connection of the latter module to the FAZ being required for the efficient integration of KIAP1 and KIAP3 into the adhesion plaque and stable Leishmania adhesion. Furthermore, this work defines the molecular architecture required for vector colonisation and identifies essential structural elements that may serve as targets for transmission-blocking interventions across kinetoplastid parasites.","abstract_has_math":false,"creators":["Omondi, Owino Barrack"],"institution":"Oxford Brookes University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Owino, Barrack Omondi","Sunter, Jack D.","Vaughan, Sue"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T03:42:02Z","subjects":[],"languages":["en"],"rights":["All rights reserved"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.24384/c1kw-5f94","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Owino, Barrack Omondi","Sunter, Jack D.","Vaughan, Sue"]},{"key":"dc:creator","label":"Author","values":["Omondi, Owino Barrack"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:publisher","label":"Institution","values":["Oxford Brookes University"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["All rights reserved"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.24384/c1kw-5f94","https://radar.brookes.ac.uk/radar/file/a05a2762-07ca-4ba0-88ea-c3a6d479f2a0/1/Owino2025LeishmaniaMexicana.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Adhesion to surfaces is a common strategy employed, especially by pathogens. In Leishmania, adhesion to the sand fly stomodeal valve is critical for infection maintenance and efficient transmission and occurs through its flagellum via a complex adhesion plaque from which filaments in the modified flagellum extend towards the cell body and likely connect to the flagellum attachment zone (FAZ), a cytoskeletal structure important for cell morphogenesis. While three essential kinetoplastid-insect adhesion proteins (KIAPs) are known, the overall proteome of the adhesion complex is obscure. Moreover, the contribution of the FAZ in adhesion and its relationship with the KIAPs remains unclear. Furthermore, in the motile Leishmania form, Myo21 is an important contributor to diverse functions, including cell morphogenesis and flagellar pocket functions. However, its roles in adhesion are unknown. Here, 17 novel adhesion plaque components that localised to the adhered flagellum were identified, including multiple members of the Adhesion Related NTPase-like Domain (ARND) family, conserved across kinetoplastids, of which the canonical member is the newly discovered KIAP4. Deletion of KIAP4 severely impaired haptomonad adhesion, with the mutant parasites unable to colonise the sand fly stomodeal valve. Deletion of FAZ2, FAZ5, and FAZ34 impaired parasite adhesion in vitro. FAZ34 deletion separated the newly identified and distinct set of KIAP2-containing extra-axonemal flagellar filaments from the anterior cell tip, resulting in haptomonad cell bodies that were positioned further from the adhesion plaque, and reduced KIAP1 and KIAP3 levels in the plaque, while the loss of the filaments through KIAP2 deletion resulted in the loss of adhesion. Moreover, Myo21 was identified as an additional component of the KIAP2-containing filaments and was essential for their organisation and integration into the adhered flagellum. Disrupting the organisation of the filaments through Myo21 deletion impaired Leishmania adhesion progression and maturation in vitro. Overall, this thesis establishes that stable haptomonad adhesion is mediated not by a single adhesive structure but by two mechanistically distinct yet functionally integrated modules: (i) a KIAP1/KIAP3/KIAP4-containing adhesion plaque positioned adjacent to the adhesion surface and (ii) a newly defined KIAP2 and Myo21-containing filament system that links the plaque to the anterior cell tip via the flagellum attachment zone (FAZ), with the connection of the latter module to the FAZ being required for the efficient integration of KIAP1 and KIAP3 into the adhesion plaque and stable Leishmania adhesion. Furthermore, this work defines the molecular architecture required for vector colonisation and identifies essential structural elements that may serve as targets for transmission-blocking interventions across kinetoplastid parasites."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Unravelling the molecular mechanisms of Leishmania mexicana adhesion in the sand fly vector"]}]}],"canonical_facts":{"dc:contributor":["Owino, Barrack Omondi","Sunter, Jack D.","Vaughan, Sue"],"dc:creator":["Omondi, Owino Barrack"],"dc:description":["Adhesion to surfaces is a common strategy employed, especially by pathogens. In Leishmania, adhesion to the sand fly stomodeal valve is critical for infection maintenance and efficient transmission and occurs through its flagellum via a complex adhesion plaque from which filaments in the modified flagellum extend towards the cell body and likely connect to the flagellum attachment zone (FAZ), a cytoskeletal structure important for cell morphogenesis. While three essential kinetoplastid-insect adhesion proteins (KIAPs) are known, the overall proteome of the adhesion complex is obscure. Moreover, the contribution of the FAZ in adhesion and its relationship with the KIAPs remains unclear. Furthermore, in the motile Leishmania form, Myo21 is an important contributor to diverse functions, including cell morphogenesis and flagellar pocket functions. However, its roles in adhesion are unknown. Here, 17 novel adhesion plaque components that localised to the adhered flagellum were identified, including multiple members of the Adhesion Related NTPase-like Domain (ARND) family, conserved across kinetoplastids, of which the canonical member is the newly discovered KIAP4. Deletion of KIAP4 severely impaired haptomonad adhesion, with the mutant parasites unable to colonise the sand fly stomodeal valve. Deletion of FAZ2, FAZ5, and FAZ34 impaired parasite adhesion in vitro. FAZ34 deletion separated the newly identified and distinct set of KIAP2-containing extra-axonemal flagellar filaments from the anterior cell tip, resulting in haptomonad cell bodies that were positioned further from the adhesion plaque, and reduced KIAP1 and KIAP3 levels in the plaque, while the loss of the filaments through KIAP2 deletion resulted in the loss of adhesion. Moreover, Myo21 was identified as an additional component of the KIAP2-containing filaments and was essential for their organisation and integration into the adhered flagellum. Disrupting the organisation of the filaments through Myo21 deletion impaired Leishmania adhesion progression and maturation in vitro. Overall, this thesis establishes that stable haptomonad adhesion is mediated not by a single adhesive structure but by two mechanistically distinct yet functionally integrated modules: (i) a KIAP1/KIAP3/KIAP4-containing adhesion plaque positioned adjacent to the adhesion surface and (ii) a newly defined KIAP2 and Myo21-containing filament system that links the plaque to the anterior cell tip via the flagellum attachment zone (FAZ), with the connection of the latter module to the FAZ being required for the efficient integration of KIAP1 and KIAP3 into the adhesion plaque and stable Leishmania adhesion. Furthermore, this work defines the molecular architecture required for vector colonisation and identifies essential structural elements that may serve as targets for transmission-blocking interventions across kinetoplastid parasites."],"dc:format":["application/pdf"],"dc:identifier":["https://doi.org/10.24384/c1kw-5f94","https://radar.brookes.ac.uk/radar/file/a05a2762-07ca-4ba0-88ea-c3a6d479f2a0/1/Owino2025LeishmaniaMexicana.pdf"],"dc:language":["en"],"dc:publisher":["Oxford Brookes University"],"dc:rights":["All rights reserved"],"dc:title":["Unravelling the molecular mechanisms of Leishmania mexicana adhesion in the sand fly vector"],"dc:type":["thesis"]},"updated_at":"2026-07-24T03:42:02Z"}