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, ␤-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.

Evidence for additive and interaction effects of host genotype and infection in malaria

“…These genes show a substantial expressed SNP (eSNP) effect in the infected group or the control group but not in both, or show the effect in opposite directions in the two different groups. Other genes subject to interaction effects beneath genome-wide significance show different magnitudes of eSNP effects between the two groups and likely have important roles in modulating the course of infection, and several of them have previously been associated with malaria (i.e., FCGR3B, PSMB9, and GSTO1) (18)(19)(20). In addition, we discovered several associations implicating key immune processes, particularly antigen processing and presentation, plasmacytoid dendritic cell activation, and T-cell activation and expansion (i.e., RAD21, LRRC25, CLEC4C SLC3A2, and TAPBP) (21-25).…”

Systems immunology of human malaria

“…The success of systems immunology studies depends on the underlying experimental design; the quality of the clinical data and biospecimens obtained; and the collaborative efforts of clinicians, epidemiologists, immunologists, bioinformaticians and computational biologists. Although important in their own right, systems approaches to animal models of malaria [22] and Plasmodium biology [23, 24] are beyond the scope of this review.…”

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

“…Infection was then induced in experimental mice by i.p. injection of 10 6 Pb2A parasites and mice were monitored for clinical systems of ECM as described previously (27)(28)(29). Parasitemia (Parasitized RBCs / Total RBCs 3 100) was determined by examining Giesma-stained thin blood films.…”