Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature

Dörpinghaus, Michael; Fürstenwerth, Finn; Roth, Lisa Katharina; Bouws, Philip; Rakotonirinalalao, Maximilian; Jordan, Vincent; Sauer, M.R.; Rehn, Torben; Pansegrau, Eva; Höhn, Katharina; Mesén-Ramírez, Paolo; Bachmann, Anna; Lorenzen, Stephan; Roeder, Thomas; Metwally, Nahla Galal; Bruchhaus, Iris

doi:10.3390/microorganisms8020174

Cited by 10 publications

(19 citation statements)

References 71 publications

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“…Transcriptome profiling showed that IEs populations enriched for binding to HBEC-5i showed exclusive expression of var2csa and the HBEC-5i enriched population bind exclusively to CSA on the surface of HBEC-5i cells (Fig. S6A) 36 . A laminar flow system was used to imitate the hydrodynamic forces exerted on IEs in blood microvessels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Exclusive expression of var2csa was confirmed by qPCR and transcriptome analysis (Fig. S6A) 36 . To select IT4-IEs CSA with knobs (IT4-IEs CSA+K ), seven rounds of enrichment were performed at 40 °C (Fig.…”

Section: Binding Behaviors To Hbec-5i Cells Under Controlled Flow Andmentioning

confidence: 87%

“…HBEC-5i, the same procedure as described above was performed. At least seven rounds of selection were performed at 37 °C and 40 °C 36 . The HBEC-5i cell line was cultivated according to ATCC guidelines.…”

Section: Selection and Enrichment Of Ies That Bind To Hbec-5i Cells mentioning

confidence: 99%

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Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Lubiana

Bouws

Roth

et al. 2020

Sci Rep

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characterizing the adhesive dynamics of Plasmodium falciparum infected erythrocytes (IEs) to different endothelial cell receptors (ECRs) in flow is a big challenge considering available methods. This study investigated the adhesive dynamics of IEs to five ECRs (CD36, ICAM-1, P-selectin, CD9, CSA) using simulations of in vivo-like flow and febrile conditions. To characterize the interactions between ECRs and knobby and knobless IEs of two laboratory-adapted P. falciplarum isolates, cytoadhesion analysis over time was performed using a new tracking bioinformatics method. The results revealed that IEs performed rolling adhesion exclusively over CD36, but exhibited stationary binding to the other four ECRs. The absence of knobs affected rolling adhesion both with respect to the distance travelled by IEs and their velocity. Knobs played a critical role at febrile temperatures by stabilizing the binding interaction. Our results clearly underline the complexity of the IE-receptor interaction and the importance of knobs for the survival of the parasite at fever temperatures, and lead us to propose a new hypothesis that could open up new strategies for the treatment of malaria. Cytoadhesion of Plasmodium falciparum to human endothelial cell receptors (ECRs) causes complications and deaths following malaria infection. In 2018, 405,000 malaria-related deaths were registered (61% of which were of children younger than 5 years old) 1. Cytoadhesion leads to accumulation of infected erythrocytes (IEs) within the microvascular bed of vital organs such as the brain, lungs, and kidneys. Death can eventually occur due to decreased blood supply and organ failure 2,3. Cytoadhesion results from interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and different ECRs 4-8. About 60 var genes per parasite genome encode PfEMP1 family members. Only one PfEMP1 variant is located on the membrane of IEs at the trophozoite stage, but the corresponding var gene is already expressed at the ring stage in a mutually exclusive pattern 9. The most studied interaction partners are the ECRs CD36, intracellular adhesion molecule 1 (ICAM-1), endothelial protein C receptor, and chondroitin sulfate A (CSA) 6,7. In general, PfEMP1 molecules cluster on nanoscale protrusions, called knobs, located on the membrane of IEs. Knobs consist of various submembranous structural proteins, predominantly knob-associated histidine-rich protein (KAHRP) 10. KAHRP contains several binding domains that interact with both parasite and host factors. Knobs begin to appear on the surface of IEs at 16 h post-invasion (hpi). The density of knobs increases from 20 to 60/µm 2 with parasite development from the

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Section: Resultsmentioning

confidence: 99%

Section: Binding Behaviors To Hbec-5i Cells Under Controlled Flow Andmentioning

confidence: 87%

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Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Lubiana

Bouws

Roth

et al. 2020

Sci Rep

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“…EC proteins, such as CD51, ICAM-1 and VCAM-1, are presented on the surface, while others, such as CD31, CD36 and CD62E, are absent [ 72 ]. In addition, HBEC-5i cells carry chondroitin sulfate A (CSA) as a dominant molecule on its surface [ 73 ]. Nevertheless, HBEC-5i exhibits essential features of cerebral EC, including tight junction structures in particular [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Cytokine Response of Human Brain Endothelial Cells after Stimulation with Malaria Patient Plasma

Raacke

Kerr

Dörpinghaus

et al. 2021

Cells

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Infections with the deadliest malaria parasite, Plasmodium falciparum, are accompanied by a strong immunological response of the human host. To date, more than 30 cytokines have been detected in elevated levels in plasma of malaria patients compared to healthy controls. Endothelial cells (ECs) are a potential source of these cytokines, but so far it is not known if their cytokine secretion depends on the direct contact of the P. falciparum-infected erythrocytes (IEs) with ECs in terms of cytoadhesion. Culturing ECs with plasma from malaria patients (27 returning travellers) resulted in significantly increased secretion of IL-11, CXCL5, CXCL8, CXCL10, vascular endothelial growth factor (VEGF) and angiopoietin-like protein 4 (ANGPTL4) if compared to matching controls (22 healthy individuals). The accompanying transcriptome study of the ECs identified 43 genes that were significantly increased in expression (≥1.7 fold) after co-incubation with malaria patient plasma, including cxcl5 and angptl4. Further bioinformatic analyses revealed that biological processes such as cell migration, cell proliferation and tube development were particularly affected in these ECs. It can thus be postulated that not only the cytoadhesion of IEs, but also molecules in the plasma of malaria patients exerts an influence on ECs, and that not only the immunological response but also other processes, such as angiogenesis, are altered.

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“…The principal and most characterised group of VSA is P. falciparum erythrocyte membrane protein 1 (PfEMP-1). P. falciparum erythrocyte membrane protein 1 is encoded by var-genes and is reported to be dominantly expressed during the asexual stage of the parasite life cycle (Agudelo et al, 2014;Chan et al, 2014) and also associated with pathogenicity of the parasite (Dörpinghaus et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Association between parasite density and cytokines in malaria infected human placentas

Okamgba

2021

Ann Med Lab Sci

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Background: Placental malaria is a major cause of infection induced adverse conditions in pregnancy and is attributed to the sequestration of malaria parasite in the intervillous space. We investigated if any relationship exists between the parasite density and cytokines in malaria parasite infected human placentas. Methods: Sixty (60) malaria parasite infected placentas from apparently healthy immediate post-partum women and 40 malaria parasite uninfected placentas which served as control were studied. Blood from the human placenta was aseptically collected and tested for HIV and malaria parasite using standard methods. Interferon-Gamma (IFNγ), Tumor Necrosis Factor alpha (TNFα), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and Interleukin-10 (IL-10) were measured by Enzyme-Linked Immunosorbent Assay (ELISA) technique. Data were analysed using appropriate statistical tools. Results: The result revealed P. falciparum with a mean parasite density of 762.47±459.62 parasite/µl of blood. The mean±SD (11.71±6.55pg/ml) and 55.57±43.13 pg/ml for IFNγ and IL-10 respectively for infected placenta was statistically higher on comparison with 5.58±2.86 pg/ml and 16.60±4.88 pg/ml for IFNγ and IL10 respectively for uninfected human placenta (P<0.05). Positive correlation existed between parasite density and IL-6 (r = 0.59, p = 0.001) and between parasite density and IL-10 (r =0.41, p=0.024). Conclusion: The study showed upregulated levels of IL-6 and IL-10 which indicates disruption of normal immune balance in the parasite infected placenta and the amount of IL-6 and IL-10 secreted could reflect the level of parasitaemia and could serve for diagnostic assessment of placental malaria.

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Stringent Selection of Knobby Plasmodium falciparum-Infected Erythrocytes during Cytoadhesion at Febrile Temperature

Cited by 10 publications

References 71 publications

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

Altered Cytokine Response of Human Brain Endothelial Cells after Stimulation with Malaria Patient Plasma

Association between parasite density and cytokines in malaria infected human placentas

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