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

Sandrine Cabantous (1, 2) , Belco Poudiougou (3) , Aurélie Bergon (4) , Abdoulaye Barry (5) , Aboubacar A Oumar (6) , Abdoulaye Traore (3) , Christophe Chevillard (4) , Ogobara Doumbo (3) , Alain Dessein (2) , Sandrine Marquet (4)

1 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
2 GIMP - Génétique et immunologie des maladies parasitaires
3 USTTB - Université des Sciences, des Techniques et des Technologies de Bamako
4 TAGC - Theories and Approaches of Genomic Complexity
5 Gabriel Toure Hospital [Bamako, Mali]
6 University of Bamako [Mali]

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.

Domaines: Sciences du Vivant [q-bio]; Médecine humaine et pathologie

Sandrine Cabantous, Belco Poudiougou, Aurélie Bergon, Abdoulaye Barry, Aboubacar A Oumar, et al.. Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction. Mediators of Inflammation, 2020, 2020, pp.1-15. ⟨10.1155/2020/3280689⟩. ⟨hal-02898283⟩