Subversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structure

Simple item page
dc.contributor.advisorMody, Christopher Hugh
dc.contributor.advisorGanguly, Anutosh
dc.contributor.authorJamil, Khusraw
dc.contributor.committeememberAmrein, Matthias W.
dc.contributor.committeememberYates, Robin Michael
dc.contributor.committeememberYong, Voon Wee
dc.date2020-11
dc.date.accessioned2020-04-29T21:59:26Z
dc.date.available2020-04-29T21:59:26Z
dc.date.issued2020-04-28
dc.description.abstractThe highly virulent fungus, Cryptococcus gattii, emerged as a novel respiratory pathogen on Vancouver Island (British Columbia, Canada) nearly two decades ago and has spread to the surrounding regions encompassing the Pacific Northwest of United States, where there is an ongoing outbreak. C. gattii is a major cause of life-threatening cryptococcosis in immunocompetent individuals and has a mortality rate of up to 33%. Host immune response is a key determining factor for the development of cryptococcal disease. It is now recognized that evasion of host immune recognition is a hallmark of C. gattii pathogenesis, but the mechanism of immune evasion remains unclear. There is increasing evidence that C. gattii subverts dendritic cell (DC) activation to evade the protective T helper cell-mediated immunity. This thesis demonstrates that primary human DC can phagocytose C. gattii yeasts but trafficking to the late phagolysosome is blocked by retention of a filamentous actin (F-actin) cage on the phagosomes. Structural studies by super resolution microscopy revealed a novel, highly branched F-actin cage that physically interfered with lysosomal fusion. C. gattii F-actin cage promoted immune evasion by silencing the canonical RelA signaling of the NF-κB pathway required for DC costimulation and T cell activation. Disruption of the F- actin cage through targeted inhibition or by TNF-α signaling reprogrammed quiescent DC to immunocompetent antigen-presenting cells (APCs). Furthermore, the presence of phagosomal F-actin cage corresponded with the presence of C. gattii polysaccharide capsule. Acapsular mutant strains did not retain phagosomal F-actin and were remarkable at inducing DC activation and T cell proliferation. Collectively, our results have uncovered a unique mechanism of DC immune subversion by intracellular pathogens such as hypervirulent C. gattii. Manipulations of this mechanism can potentially inform novel therapeutic interventions against C. gattii.en_US
dc.identifier.citationJamil, K. (2020). Subversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structure (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37742
dc.identifier.urihttp://hdl.handle.net/1880/111926
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectDendritic cellen_US
dc.subjectCryptococcusen_US
dc.subjectFungusen_US
dc.subjectImmune evasionen_US
dc.subject.classificationMicrobiologyen_US
dc.subject.classificationImmunologyen_US
dc.titleSubversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structureen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Immunologyen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
ucalgary_2020_jamil_khusraw.pdf
Size:
72.49 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2.62 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Open Theses and Dissertations