Plasmodium falciparum PfEMP1 Modulates Monocyte/Macrophage Transcription Factor Activation and Cytokine and Chemokine Responses

Abstract

Immunity to Plasmodium falciparum malaria is slow to develop, and it is often asserted that malaria suppresses host immunity, although this is poorly understood and the molecular basis for such activity remains unknown. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a virulence factor that plays a key role in parasite-host interactions. We investigated the immunosuppressive effect of PfEMP1 on monocytes/macrophages, which are central to the antiparasitic innate response. RAW macrophages and human primary monocytes were stimulated with wild-type 3D7 or CS2 parasites or transgenic PfEMP1-null parasites. To study the immunomodulatory effect of PfEMP1, transcription factor activation and cytokine and chemokine responses were measured. The level of activation of NF-κB was significantly lower in macrophages stimulated with parasites that express PfEMP1 at the red blood cell surface membrane than in macrophages stimulated with PfEMP1-null parasites. Modulation of additional transcription factors, including CREB, also occurred, resulting in reduced immune gene expression and decreased tumor necrosis factor (TNF) and interleukin-10 (IL-10) release. Similarly, human monocytes released less IL-1β, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and TNF specifically in response to VAR2CSA PfEMP1-containing parasites than in response to PfEMP1-null parasites, suggesting that this immune regulation by PfEMP1 is important in naturally occurring infections. These results indicate that PfEMP1 is an immunomodulatory molecule that affects the activation of a range of transcription factors, dampening cytokine and chemokine responses. Therefore, these findings describe a potential molecular basis for immune suppression by P. falciparum.

Extracellular vesicles from early stagePlasmodium falciparum-infected red blood cells contain PfEMP1 and induce transcriptional changes in human monocytes

“…However, the response to ring‐stage iRBC‐EVs was not evaluated. We have recently shown that PfEMP1 located on the iRBC surface can specifically modulate the monocyte immune response to parasites (Sampaio, Eriksson, et al, ). However, to investigate whether the presence of PfEMP1 in ring‐stage iRBC‐EVs had a similar effect on monocytes, the optimal EV concentration for cell stimulation was first determined by flow cytometry to achieve the highest response (iRBC‐EV) to background (uRBC‐EV) signal (Figure S2).…”

“…Namely, stimulus with PfEMP1‐negative iRBC‐EVs induced nearly three‐fold more gene expression changes compared to PfEMP1‐positive iRBC‐EVs and upregulated pathways involving “defence response,” “cellular response to cytokine stimulus,” and “response to stress,” which were not upregulated with the PfEMP1‐positive iRBC‐EVs. PfEMP1, when in the biologically relevant concentrations and cellular localisation of the iRBC surface, inhibits monocyte responses (Sampaio, Eriksson, et al, ). It is possible that PfEMP1 could also exert an immune modulatory effect on monocytes when delivered via EVs.…”

“…This adherence is a major contributor to P. falciparum pathogenesis and can lead to particularly severe complications when sequestration occurs in blood vessels of the brain (Jensen et al, 2004;Tembo et al, 2014). Furthermore, PfEMP1 can dampen cytokine release from NK cells, γδ T cells (D'Ombrain et al, 2007), and monocytes (Sampaio, Eriksson, & Schofield, 2017). PfEMP1 is produced early in the intraerythrocytic life cycle, already detectable in the parasite 8-hr postinvasion, and is shuttled through Maurer's Clefts to appear at the iRBC surface from 16-hr postinvasion (Kriek et al, 2003;McMillan et al, 2013).…”

<p>Immunoinformatics and Vaccine Development: An Overview</p>

“…These proteins function to assist the parasite to evade destruction by the host immune systems. 95,96 The PfEMP1 proteins were identified as the prime ligands responsible for cytoadherence and resetting. 97 They cause the infected RBCs of host tissues to sequester thus helping the parasite to circumvent clearance by the host's spleen.…”

Diagnóstico y manejo de la restricción del crecimiento intrauterino en fetos de gestantes provenientes de zonas endémicas para la malaria

“…y por ende no desarrolla una inmunidad efectiva en comparación con las multigestantes 24 , además, la concentración de hormonas sexuales y el cortisol, tienden a disminuir a medida que aumenta la paridad 10,19,18 Fisiopatología de malaria placentaria Los eritrocitos infectados por Plasmodium spp., expresan un antígeno variante en su membrana, denominado -Plasmodium falciparum erythrocyte membrane protein 1-(PfEMP1) 25 , que facilita la adhesión de las células infectadas a receptores de condroitín sulfato A (CSA), presentes en la placenta 26 ; esta unión facilita el ingreso y secuestro del patógeno en el espacio intervelloso 27 , allí se desencadena una respuesta inmune pro-inflamatoria, mediada inicialmente por la liberación de TNF-α por parte de las células natural killer uterinas (NKu), que tiene un efecto químioatrayente sobre monocitos y macrófagos para amplificar la respuesta inmunitaria TH1 , en un intento por defender el contexto placentario contra la infección 19 .…”