title: Molecular correlates of experimental cerebral malaria detectable in whole blood.
abstract: Cerebral malaria (CM) is a primary cause of deaths caused by Plasmodium falciparum in young children in sub-Saharan Africa. Laboratory tests based on early detection of host biomarkers in patient blood would help in the prognosis and differential diagnosis of CM. Using the Plasmodium berghei ANKA murine model of experimental cerebral malaria (ECM), we have identified over 300 putative diagnostic biomarkers of ECM in the circulation by comparing the whole-blood transcriptional profiles of resistant mice (BALB/c) to those of two susceptible strains (C57BL/6 and CBA/CaJ). Our results suggest that the transcriptional profile of whole blood captures the molecular and immunological events associated with the pathogenesis of disease. We find that during ECM, erythropoiesis is dysfunctional, thrombocytopenia is evident, and glycosylation of cell surface components may be modified. Furthermore, analysis of immunity-related genes suggests that slightly distinct mechanisms of immunopathogenesis may operate in susceptible C57BL/6 and CBA/CaJ mice. Furthermore, our data set has allowed us to create a molecular signature of ECM composed of a subset of circulatory markers. Complement component C1q, β-chain, nonspecific cytotoxic cell receptor protein 1, prostate stem cell antigen, DnaJC, member 15, glutathione S-transferase omega-1, and thymidine kinase 1 were overexpressed in blood during the symptomatic phase of ECM, as measured by quantitative real-time PCR analysis. These studies provide the first host transcriptome database that is uniquely altered during the pathogenesis of ECM in blood. A subset of these mediators of ECM warrant validation in P. falciparum-infected young African children as diagnostic markers of CM.
authors.affiliation: Division of Bacterial, Parasitic, and Allergenic Products Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA.
authors.forename: Miranda S
authors.initials: MS
authors.lastname: Oakley
authors.forename: Vivek
authors.initials: V
authors.lastname: Anantharaman
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Venancio
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Babita
authors.initials: B
authors.lastname: Mahajan
authors.forename: Victoria
authors.initials: V
authors.lastname: Majam
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McCutchan
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D016779:Malaria, Cerebral / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D046228:Microarray Analysis; D010962:Plasmodium berghei / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers