Scientific Publications by FDA Staff

Infect Immun 2011 Mar;79(3):1244-53

Molecular correlates of experimental cerebral malaria detectable in whole blood.

Oakley MS, Anantharaman V, Venancio TM, Zheng H, Mahajan B, Majam V, McCutchan TF, Myers TG, Aravind L, Kumar S

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 P. 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 (BALB/c) mice to 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 dataset has allowed us to create a molecular signature of ECM composed of a subset of circulatory markers. Complement component C1q, ß chain, non-specific 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.