Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

Abstract

Background. Cerebral malaria (CM), a reversible encephalopathy affecting young children, is a medical emergency requiring rapid clinical assessment and treatment. However, understanding of the genes/proteins and the biological pathways involved in the disease outcome is still limited. Methods. We have performed a whole transcriptomic analysis of blood samples from Malian children with CM or uncomplicated malaria (UM). Hierarchical clustering and pathway, network, and upstream regulator analyses were performed to explore differentially expressed genes (DEGs). We validated gene expression for 8 genes using real-time quantitative PCR (RT-qPCR). Plasma levels were measured for IP-10/CXCL10 and IL-18. Results. A blood RNA signature including 538 DEGs (∣FC∣≥2.0, adjusted P value ≤ 0.01) allowed to discriminate between CM and UM. Ingenuity Pathway Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed novel genes and biological pathways related to immune/inflammatory responses, erythrocyte alteration, and neurodegenerative disorders. Gene expressions of CXCL10, IL12RB2, IL18BP, IL2RA, AXIN2, and NET were significantly lower in CM whereas ARG1 and SLC6A9 were higher in CM compared to UM. Plasma protein levels of IP-10/CXCL10 were significantly lower in CM than in UM while levels of IL-18 were higher. Interestingly, among children with CM, those who died from a complication of malaria tended to have higher concentrations of IP-10/CXCL10 and IFN-γ than those who recovered. Conclusions. This study identified some new factors and mechanisms that play crucial roles in CM and characterized their respective biological pathways as well as some upstream regulators.

Transcriptome-based analysis of blood samples reveals elevation of DNA damage response, neutrophil degranulation, cancer and neurodegenerative pathways in Plasmodium falciparum patients

“…This means MM and some neurodegenerative diseases may share parallel biological processes, which is contradictory to the findings of Thiam et al . [ 28 ] and Cabantous et al [ 29 ], where neurodegenerative pathways were found in CM only. Nonetheless, processes involved in cancer, EBV infection and DNA damage repair were the most significant.…”

“…and Cabantous et al . demonstrated the activation of genes associated with AD and PD in CM [ 28 , 29 ]. In addition, Boldt et al .…”

Inflammation and Cellular Stress Induced Neurological Sequelae ofPlasmodium falciparumMalaria

“…The protein interaction network besides relevant sub-networks of IL-18 signaling and the blood group proteins XK and KEL regulating axon diameter showed a large connected area centered by TUBB2A and the Metalloproteinases 8 and 9 (MMP8, MMP9). TUBB2A has been reported to be up-regulated in CM by Cabantous et al [29] as part of the Parkin-Ubiquitin proteasome degradation pathway which when impaired can be deleterious to dopaminergic neurons [114].…”

“…The copyright holder for this preprint this version posted June 16, 2021. ; https://doi.org/10.1101/2021.06. 16.448682 doi: bioRxiv preprint and Cabantous et al demonstrated the activation of genes associated with AD and PD in CM [28,29]. In addition, Boldt et al found a signature of 22 differentially expressed genes related to immunopathological processes and complement regulation in the transcriptome of distinct conditions of childhood malaria including CM [30].…”

Blood Transcriptomics of Turbot Scophthalmus maximus: A Tool for Health Monitoring and Disease Studies

“…As molecular processes driving complex diseases usually involve sets of genes acting in a concerted way, one strategy is to use high-throughput “omics” technologies to simultaneously investigate thousands of genes in a pathological context [ 6 ]. In human medicine, it has been observed that the analysis of the blood transcriptome can provide a comprehensive view of the state of the immune system, advance our understanding of disease pathogenesis and highlight potential biomarkers to be used in diagnosis, prognosis and treatment monitoring [ 5 , 7 , 8 ].…”