Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/142942
Full metadata record
DC FieldValueLanguage
dc.contributor.authorChew, Marvinen_US
dc.date.accessioned2020-07-14T07:36:47Z-
dc.date.available2020-07-14T07:36:47Z-
dc.date.issued2019-
dc.identifier.citationChew, M. (2019). Adaptation of Plasmodium falciparum in human RBC supplemented NSG mice. Doctoral thesis, Nanyang Technological University, Singapore.en_US
dc.identifier.urihttps://hdl.handle.net/10356/142942-
dc.description.abstractHuman chimeric mouse models, also known as humanized mice, are powerful tools to study human obligate pathogens such as Plasmodium falciparum. In our chimeric mouse model, human RBC supplemented NSG mice, static in vitro cultured P. falciparum require adaptation to become competent to thrive in the mice. During the adaptation process, variant surface antigens (VSAs), known to play a major role in virulence and antigenic variation are upregulated. These VSAs belong to large multigenic families such as P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) and Repetitive Interspersed Family proteins (RIFINs) that have been shown to immune modulate effector function of host immune cells. Adapted parasite upregulates VAR2CSA PfEMP1, a known immune modulator of macrophages. Using an in vivo conditional knockdown of P. falciparum membrane-associated histidine rich protein 1 (MAHRP1), surface expression of PfEMP1 was affected and diminished in adapted P. falciparum. This led to reduced competency of adapted parasites in the huRBC-NSG mice. In vitro phagocytosis assay also showed that adapted parasites are less recognized and phagocytosed by mouse and human macrophages compared to non-adapted parasites. MAHRP1 knockdown of adapted parasites also resulted in increased macrophage recognition and phagocytosis. We utilized the phagocytosis assay to screen known macrophage-polarizing compounds for increased phagocytosis of adapted parasites. Three compounds that polarize macrophages towards M1-like and three towards M2-like macrophages were able to increase phagocytosis of adapted parasites after 24-hour treatment of M0 human primary macrophages. Adapted parasites also upregulate A-type RIFINs that have been shown recently to ligate host immune inhibitory receptor, leucocyte immunoglobulin-like receptor B1 (LILRB1). Adapted parasites are less controlled by primary responder NK cell compared to non-adapted parasites. Moreover, anti-LILRB1 blocking antibody partially restores NK cell control of adapted parasites, indicating that LILRB1 is involved in the reduction of NK cell control of adapted parasites. Therefore, adapted P. falciparum infection in huRBC-NSG mice provides a powerful tool to elucidate host immune modulatory mechanisms of P. falciparum and provides new approaches for therapy and treatment.en_US
dc.language.isoenen_US
dc.publisherNanyang Technological Universityen_US
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).en_US
dc.subjectScience::Biological sciences::Microbiology::Immunologyen_US
dc.subjectScience::Biological sciences::Molecular biologyen_US
dc.titleAdaptation of Plasmodium falciparum in human RBC supplemented NSG miceen_US
dc.typeThesis-Doctor of Philosophyen_US
dc.contributor.supervisorPeter Preiseren_US
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.description.degreeDoctor of Philosophyen_US
dc.contributor.researchSingapore-MIT Alliance Programmeen_US
dc.contributor.supervisoremailPRPreiser@ntu.edu.sgen_US
item.fulltextWith Fulltext-
item.grantfulltextopen-
Appears in Collections:SBS Theses

Page view(s)

54
checked on Oct 24, 2020

Download(s)

7
checked on Oct 24, 2020

Google ScholarTM

Check

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.