Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Plasmodium Falciparum Homo Sapiens (human)

TISSUE(S): Erythrocyte, Blood

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Virginie Salnot

LAB HEAD: Gwladys I.

PROVIDER: PXD042503 | Pride | 2024-02-01

REPOSITORIES: Pride

ACCESS DATA

Similar Datasets

Project description:Cerebral malaria (CM) lethality is attributable to brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored. Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in cerebral malaria (CM) development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing, and folding and antigen presentation. In vitro assays show that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation, and Wnt/ ß-catenin signaling. Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and fatty acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Our results unveiled that Type 1 IFN signaling and subsequent immunoproteasome activation in BECs contribute to enhanced antigen presentation and the impairment of the endothelial barrier function. We also show that Type 1 IFN signaling and its downstream effects are licensed by dramatic increase in glucose uptake with an impact on energy metabolism pathways. This work raises the hypothesis that Type 1 IFN- immunoproteasome induction response in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells, which is a determinant of brain cytotoxic edema and (2) by promoting endothelial barrier dysfunction, that likely favors brain vasogenic edema.

Project description:In temperate and sub-tropical regions of Latin America, complicated malaria manifested as hepatic dysfunction or renal dysfunction is seen in all age groups. There has been a concerted focus on understanding the patho-physiological and molecular basis of complicated malaria in children, much less is known about it in adults. This can be attributed to many factors: one of which is the expression of clonally variant families of adhesion proteins: PfEMP1 on the iRBC surface. We report here, the analysis of data from a custom, cross strain microarray (Agilent Platform) using material from patient samples, showing hepatic dysfunction or renal failure. These are the most common manifestations seen in adults along with cerebral malaria. The data has been analyzed with reference to variable surface antigens, encoded by the var, rifin and stevor gene families. The differential regulation profiles of key genes (comparison of PFC and PFU) have been observed. The exportome has been analyzed using similar parameters. GO term based functional enrichment of differentially regulated genes identified, up-regulated genes stastically enriched (p<0.5) to critical biological processes. Systems network based functional enrichment of overall differentially regulated genes yielded a similar result. We are reporting here, up-regulation of var group A and B genes whose proteins are predicted to interact with CD36 receptor in the host as also the up-regulation of group A rifins and many of the stevors. This is contrary to most other reports from pediatric patients, with cerebral malaria where the up-regulation of var A group genes have been seen. A protein-protein interaction based network has been created and analysis performed. This co-expression and text mining based network has shown overall connectivity between the variable surface antigens and the exportome. The up-regulation of var group B and C genes encoding PfEMP1 with different domain architecture would be important for deciding strategies for disease prevention. Plasmodium falciparum isolates were collected from patients (n=12) with differing clinical conditions. The patients exhibited symptoms categorized as uncomplicated (n=5) or complicated malaria (n=7). Criteria for determination of complicated disease were based on World Health Organization year 2000 guidelines. Microarray array based transcriptional profiling was carried out to find out differentailly expressed genes in complicated malaria isolates (non-cerebral malaria) compared to un-complicated malaria isolates.

Project description:Micronutrient deficiencies and environmental exposures have been to known to adversely impact brain and nervous system functions in adults and children worldwide. However, few studies have examined the short and long-term impact of these risk factors on neurodevelopmental outcomes in children in low-income countries, where the effects are likely to be more pronounced due to limited resources for monitoring and insufficient regulations. Biological risk factors of relevance include micronutrient deficiencies such as zinc and exposure to heavy metals such as lead and mercury. Studies have suggested an association between neurodevelopmental impairment and micronutrient deficiency as well as exposure to a number of heavy metals and environmental toxins. Moreover, findings also suggest that risk factors for adverse developmental outcomes that are independently significant may have the potential for causing cumulative increases in adverse effects. In Sub-Saharan Africa, severe malaria is a leading risk factor for long-term neurocognitive impairment in children. Zinc deficiency or exposure to heavy metals could influence risk of severe malaria, modify the risk of neurocognitive impairment in children with severe malaria, or independently affect risk of neurocognitive impairment. Untargeted analyses for potential environmental exposures or metabolomic changes in children with cerebral malaria vs. without cognitive impairment or in children with higher vs. lower cognitive scores, could also identify new risk factors for neurodevelopmental impairment in Ugandan children with cerebral malaria.In our completed study in Kampala, we assessed neurologic and developmental impairment in children with cerebral malaria [CM] or severe malarial anemia [SMA], as compared to health community children from the same extended household as the children with CM or SMA. As an extension of this study, we are interested in determining levels of micronutrients such as zinc in the population, and in addition, determining exposure levels of heavy metals (lead, mercury, copper, manganese etc.) in samples collected from children with severe malaria and community controls. The primary hypotheses of this study is that nutrient deficiencies or exposure to heavy metals influence short and long term neurocognitive outcomes in healthy community children and in children with severe malaria, and that children with cerebral malaria have specific metabolomic changes that relate to long-term neurocognitive impairment. The specific aims of our study are:Aim 1: To determine levels of zinc, heavy metals, and biomarkers associated with inflammation in children presenting with different forms of severe malaria (SM) and in healthy community children (CC). The working hypothesis of this aim is that 1) children with SM will have lower zinc levels compared to CC; 2) children with SM will present with higher toxic metal exposure and higher levels of biomarkers associated with inflammation than CC.Aim 2: To investigate how micronutrient deficiency, toxic metal exposure and inflammatory biomarkers affect short and long term neurodevelopmental outcomes and growth in children with severe malaria and community children (CC).The working hypothesis of this aim is that the lower levels of zinc, and presence of toxic metals in high concentrations will independently contribute to worsening neurodevelopmental outcomes and worsening growth over time in children with severe malaria and in community children. An alternate hypothesis is that micronutrient deficiency, toxic metal exposure and inflammatory states may interact with each other and with severe malaria to produce greater neurodevelopmental impairment, i.e., that the contribution is not independent but interactive.Aim 3: To determine whether the CSF metabolome differs according to level of neurodevelopmental impairment in children with cerebral malaria. The working hypothesis of this aim is that neurodevelopmental impairment in children with cerebral malaria is associated with changes in the CSF metabolome.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure