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Infected erythrocytes and plasma proteomics reveals a specific protein signature of severe malaria

ABSTRACT: Cerebral malaria (CM), the most lethal complication of Plasmodium falciparum severe malaria (SM), remains fatal for 15 to 25% of affected children despite the availability of treatment. P. falciparum infects and multiplies in erythrocytes, contributing to anemia, parasite sequestration, and inflammation. An unbiased proteomic assessment of infected erythrocytes and plasma samples from 24 Beninese children was performed to study the complex mechanisms underlying CM. A significant down-regulation of proteins from the ubiquitin-proteasome pathway and an up-regulation of the erythroid precursor marker transferrin receptor protein 1 (TFRC) were associated with infected erythrocytes from CM patients. At the plasma level, the samples clustered according to clinical presentation. Significantly, increased levels of the 20S proteasome components were associated with SM. Targeted quantification assays confirmed these findings on a larger cohort (n=340). These findings suggest that parasites causing CM preferentially infect reticulocytes or erythroblasts and alter their maturation. Importantly, the host plasma proteome serves as a specific signature of SM and presents a remarkable opportunity for developing innovative diagnostic and prognostic biomarkers.

SUBMITTER: Jérémy Fraering

PROVIDER: S-SCDT-10_1038-S44321-023-00010-0 | biostudies-other |

REPOSITORIES: biostudies-other

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Infected erythrocytes and plasma proteomics reveal a specific protein signature of severe malaria

Project description:Cerebral malaria (CM), the most lethal complication of Plasmodium falciparum severe malaria (SM), claims the life of 15 to 25% of admitted children despite treatment. P. falciparum infects and multiplies in human erythrocytes, contributing to anemia, parasite sequestration, and inflammation in the host. In this study, an unbiased proteomic assessment of infected erythrocytes and plasma samples from 24 Beninese children was performed to decipher the complex mechanisms underlying the pathophysiology of CM and the corresponding host-parasite interactions. A significant down-regulation of proteins from the ubiquitin-proteasome pathway and an up-regulation of the erythroid precursor marker transferrin receptor protein 1 (TFRC) was associated with infected erythrocytes from CM patients. Further functional analysis showed dysregulated iron metabolism and ferroptosis pathways associated with CM. At the plasma level, the samples clustered according to clinical presentation. Importantly, increased levels of the 20S proteasome components were associated with SM. Targeted quantification assays confirmed these findings on a larger confirmation cohort (n=274). These findings suggest that parasites causing CM preferentially infect reticulocytes or erythroid precursors and alter their maturation. Importantly, the host plasma proteome serves as a specific signature of SM and presents a remarkable opportunity for developing innovative diagnostic and prognostic biomarkers.

2024-02-01 | PXD043033 | Pride

Infected erythrocytes and plasma proteomics reveal a specific protein signature of severe malaria.

Project description:Severe malaria (SM) is a life-threatening condition caused by Plasmodium falciparum and the most severe presentation is cerebral malaria (CM) mostly affecting children under five years old. The comprehensive understanding of the complex mechanisms driving the pathophysiology of CM, which encompasses both host and parasite factors, remains insufficiently elucidated. This study analyzed clinical isolates from Beninese children using liquid chromatography-mass spectrometry to identify differentially expressed proteins in SM compared to uncomplicated malaria (UM) patients. We showed a down-regulation of proteins involved in ubiquitination and proteasomal protein degradation in infected erythrocytes from CM patients. In plasma we observed that proteasome 20S components were more abundant in SM patients, which could potentially be useful as a severity biomarker. Furthermore, transferrin receptor protein 1 was specifically upregulated in CM infected erythrocyte isolates which raises the hypothesis that parasites causing CM could preferably infect reticulocytes or erythroid precursors. Consistently with this hypothesis we also found that parasite proteins implicated in distinct biosynthesis pathways were upregulated in CM. Moreover, functional analysis showed deregulated iron metabolism and ferroptosis pathways associated with CM presentation. Further investigations are required to confirm these findings and determine their potential for clinical application.

2024-02-01 | PXD042503 | Pride

Quantitative proteomics reveals specific protein regulation of severe hypospadias.

Project description:BackgroundThe etiological mechanism of hypospadias is multifactorial and may be heterogeneous by severity. To date, very limited analyses on proteome in hypospadias have been conducted, and there are still no severe hypospadias proteomics analyses.MethodsIn our study, tandem mass tag (TMT)-based quantitative proteomics was performed, exploring the clinical samples from hypospadias patients and healthy donators, in order to identify distinctly expressed proteins for severe hypospadias. To further uncover the mechanistic links in these complex proteomics data, we performed several core ingenuity pathway analyses (IPA) to predict, based on these observed different expression of proteins (DEPs).ResultsCompared with the unaffected controls, 299 proteins were found to be down-regulated and 176 proteins up-regulated in severe hypospadias foreskin tissues. Functional annotation revealed that these DEPs were mainly in the extracellular space and were associated with complement activation and coagulation cascades. Similarly, the IPA core analysis revealed enriched pathways of the acute phase response signaling and complement system, demonstrating that by mediating their targeted, differentiated expressed proteins (A2M, APOE, C4A/C4B, C5, CAT, CD74, CFP, CREB1, CTSB, FGA, FGB, FGG, FN1, FOS, HP, LYZ, PF4, RBP1, S100A12, SERPINA3, SLC2A1, and THBS1) may be involved in the activation of myeloid cell degranulation, phagocytes degranulation, molecule secretion, and were mainly regulated by CSF1, JNK, STAT1, and STAT3.ConclusionsOur findings raise questions regarding the role of inflammatory activity in the pathology of severe hypospadias. This approach highlights the possibility of the use of non-surgical approaches to limit fibrotic signals and function, which is a promising potential therapeutic strategy for hypospadias patients.

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Electrophysiological studies of malaria parasite-infected erythrocytes: current status.

Project description:The altered permeability characteristics of erythrocytes infected with malaria parasites have been a source of interest for over 30 years. Recent electrophysiological studies have provided strong evidence that these changes reflect transmembrane transport through ion channels in the host erythrocyte plasma membrane. However, conflicting results and differing interpretations of the data have led to confusion in this field. In an effort to unravel these issues, the groups involved recently came together for a week of discussion and experimentation. In this article, the various models for altered transport are reviewed, together with the areas of consensus in the field and those that require a better understanding.

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Project description:Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.

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Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity.

Project description:Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

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