Malaria is a severe global health problem that causes approximately 435,000 deaths per year. Any non-immune individual traveling to malaria endemic regions can be affected too, including humanitarian volunteers, travelers, and US troops.
Under physiological conditions, damaged or malaria-infected RBCs would be removed within the spleen, but Plasmodium falciparum infected RBCs (iRBCs) sequester to microvascular endothelial cells to avoid entering the spleen. Adhesion interactions and parasite sequestration to endothelial cells are mediated by Plasmodium falciparum erythrocyte membrane protein 1 family (PfEMP1) proteins expressed on the iRBC’s surface. The PfEMP1 proteins bind to existing endothelial cell surface receptors that already serve primary functions, including ICAM-1, integrin αVβ3, and CD36.
Traditionally, these receptors are explored in the context of endothelial cell sequestration, but this project examines the consequence of receptor::PfEMP1 interaction on immune cells, namely monocyte-like THP-1 cells.
Since most deaths occur when non-immune individuals are exposed to the parasite, it is important to investigate the interaction the naïve immune system will have, when first encountering a PfEMP1-expressing iRBC. The circulating innate immune monocyte’s ability to travel through the bloodstream, increases the probability of encountering an iRBC and serves as an interesting target to further understand the naïve host’s initial reaction to malaria infection. We incubated THP-1 cells or soluble ICAM-1, integrin αVβ3, and CD36 receptors with PfEMP1-coated 5µm beads, surface-immobilized PfEMP1 proteins, and iRBCs to simulate the host’s naïve interaction toward IRBCs in vitro. Using strong ICAM-1, integrin αVβ3, and CD36 binding PfEMP1 proteins, we determined if PfEMP1 overall protein sequence similarity has an effect on binding strength, if binding strength leads to a stronger ability to ligate to our target receptors and THP-1 cells, and if this ligation will result in an inflammatory immune response by monocyte-like THP-1 cells to eliminate the parasite.
Our study determined that overall protein sequence similarity toward the strong CD36 binding PfEMP1 protein was correlated with CD36-binding strength and ability to ligate to CD36 on a monocyte-like THP-1 cell. Overall sequence similarity did not predict ability of PfEMP1 proteins to bind to ICAM-1 and integrin αVβ3. Ligation of THP-1 to surface-immobilized ICAM-1, integrin αVβ3, and CD36 strong binding PfEMP1 proteins produced mainly anti-inflammatory effects. Incubation of THP-1 cells with live iRBCs, which bind to ICAM-1 (3G8 line), integrin αVβ3 (E9 line), and CD36 (E9 line) produced mainly pro-inflammatory effects. We speculate that the resulting pro-inflammatory effects might have been partially limited by the anti-inflammatory effects of PfEMP1::THP-1 ligation through our target receptors.
|Commitee:||Hartmann, James, Iragavarapu, Vijaya, Shibata, Yoshimi|
|School:||Florida Atlantic University|
|School Location:||United States -- Florida|
|Source:||DAI-B 81/6(E), Dissertation Abstracts International|
|Subjects:||Parasitology, Molecular biology, Immunology|
|Keywords:||CD36, ICAM-1, Integrin αVβ3, PfEMP1, Plasmodium falciparum, THP-1|
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