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|Title:||Adaptation of Plasmodium falciparum in human RBC supplemented NSG mice||Authors:||Chew, Marvin||Keywords:||Science::Biological sciences::Microbiology::Immunology
Science::Biological sciences::Molecular biology
|Issue Date:||2019||Publisher:||Nanyang Technological University||Source:||Chew, M. (2019). Adaptation of Plasmodium falciparum in human RBC supplemented NSG mice. Doctoral thesis, Nanyang Technological University, Singapore.||Abstract:||Human 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.||URI:||https://hdl.handle.net/10356/142942||Rights:||This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
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