Biology subjects

Franke-Fayard, B.

Publications and source records attributed to Franke-Fayard, B..

4 recordsLinked to original sources

bioRxiv2024

Erythrocyte membrane protein 3 (EMAP3) is exposed on the surface of the Plasmodium berghei infected red blood cell

The human malaria parasite Plasmodium falciparum invades red blood cells (RBC) and exports parasite proteins to transform the host cell for its survival. These exported proteins facilitate uptake of nutrients and cytoadherence of the infected RBC (iRBC) to endothelial cells of small blood vessels, thus protecting the iRBC from splenic clearance. The parasite protein PfEMP1 and the host protein CD36 play a major role in P. falciparum iRBC cytoadherence. The murine parasite Plasmodium berghei is a widely used experimental model that combines high genetic tractability with access to in vivo studies. P. berghei iRBC also sequesters in small blood vessels, mediated by binding to CD36. However, the parasite proteins binding to CD36 are unknown and only very few parasite proteins, including EMAP1 and EMAP2, have been identified that are present at the iRBC membrane. We have identified a new protein named EMAP3 and demonstrated its export to the iRBC membrane where it interacts with EMAP1, with only EMAP3 exposed on the outer surface of the iRBC. Parasites lacking EMAP3 display no significant reduction in growth or sequestration, indicating that EMAP3 is not the major CD36-binding protein. The outer-surface location of EMAP3 offers a new scaffold for displaying P. falciparum proteins on the surface of the P. berghei iRBC, providing a platform to screen in vivo putative inhibitors of P. falciparum cytoadherence.

microbiology↗

bioRxiv2022

Downregulation of the secreted protein with an altered thrombospondin repeat (SPATR) impacts the infectivity of malaria sporozoites

The identification of surface proteins of the sporozoite stage of malaria parasites important for sporozoite infectivity could aid in the improvement of the efficacy of vaccines targeting pre-erythrocytic stages. Thus, we set out to disclose the role of the secreted protein with an altered thrombospondin repeat (SPATR), which is highly expressed in sporozoites. Previous studies showed an essential function in blood stages, while no role was detected in sporozoites despite high expression. To achieve downregulation of expression in sporozoites while maintaining blood stage expression, a promoter swap approach was used to generate a mutant where the Plasmodium berghei spatr gene was placed under transcriptional control of the hado gene promoter. Downregulation of expression in oocysts and sporozoites resulted in formation of sporozoites with impaired motility, strongly reduced capacity to invade salivary glands, and decreased infectivity to mice. In conclusion, we revealed a new role for SPATR in sporozoite infectivity, highlighting the importance to use complementary methods in studies on sporozoite biology.

microbiology↗

bioRxiv2021

Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria

Malaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient (Cd74-/-) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels from Cd74-/- hosts to present parasite antigen to sequestered Plasmodium-specific CD8+ T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.

microbiology↗

bioRxiv2019

Transcriptome analysis of Plasmodium berghei during exo-erythrocytic development

The complex life cycle of malaria parasites requires well-orchestrated stage specific gene expression. In the vertebrate host the parasites grow and multiply by schizogony in two different environments: within erythrocytes and within hepatocytes. Whereas erythrocytic parasites are rather well-studied in this respect, relatively little is known about the exo-erythrocytic stages. In an attempt to fill this gap, we performed genome wide RNA-seq analyses of various exo-erythrocytic stages of Plasmodium berghei including sporozoites, samples from a time-course of liver stage development and detached cells, which contain infectious merozoites and represent the final step in exo-erythrocytic development. The analysis represents the completion of the transcriptome of the entire life cycle of P. berghei parasites with temporal detailed analysis of the liver stage allowing segmentation of the transcriptome across the progression of the life cycle. We have used these RNA-seq data from different developmental stages to cluster genes with similar expression profiles, in order to infer their functions. A comparison with published data of other parasite stages confirmed stage-specific gene expression and revealed numerous genes that are expressed differentially in blood and exo-erythrocytic stages. One of the most exo-erythrocytic stage-specific genes was PBANKA_1003900, which has previously been annotated as a "gametocyte specific protein". The promoter of this gene drove high GFP expression in exo-erythrocytic stages, confirming its expression profile seen by RNA-seq. The comparative analysis of the genome wide mRNA expression profiles of erythrocytic and different exo-erythrocytic stages improves our understanding of gene regulation of Plasmodium parasites and can be used to model exo-erythrocytic stage metabolic networks and identify differences in metabolic processes during schizogony in erythrocytes and hepatocytes.

microbiology↗