Cerebral Malaria Pathogenesis

Abstract

Cerebral malaria (CM) attributable to Plasmodium falciparum infection is estimated to affect 575,000 children in sub-Saharan Africa every year 1 and is among the deadliest forms of malaria, with an average estimated mortality rate of 18.6%. 2 Although extensive studies have been conducted in murine models of CM and in human populations with CM, the pathogenesis of CM is still incompletely understood. Studies to date suggest that CM is attributable to a combination of local brain tissue damage from microvascular ischemia and hypoxia and more global brain injury caused by the host immune response to the parasite. 3 A deficiency of most murine and human CM studies is that assessment has been restricted to specific predefined factors hypothesized to be of importance. These studies address specific hypotheses but cannot provide a systemic evaluation of the potential factors in the pathogenesis of CM.Systems biology, in particular the decoding of the human and murine genome, development of microarray analysis, and application of more sophisticated computational technology to assess the results of this analysis, has moved us ahead in our understanding of numerous diseases. In an elegant and carefully designed series of experiments in this issue of The American Journal of Pathology, Lovegrove and colleagues 4 use microarray analysis of whole brain tissue gene expression in CM-susceptible and CM-resistant mice to define potential pathways involved in murine CM pathogenesis. Their microarray analysis and confirmatory quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry studies demonstrate that interferon (IFN)-regulated processes and neuronal apoptosis appear to be important in murine CM pathogenesis. These findings, particularly the findings about neuronal apoptosis, are novel and add significantly to our understanding of murine CM pathogenesis. Although there are important differences between murine CM models and human CM, these findings may also provide clues about human CM pathogenesis and, in particular, suggest potential mechanisms for the long-term cognitive sequelae that occur in children with CM. 5,6 Differences between Murine CM Models and Human CM As is the case for many diseases affecting the brain, far more is known about the pathogenesis of murine CM than human CM. The most obvious reason for this is that sizeable numbers of murine brains can be studied at different phases of the illness, but human brain studies of CM are limited to those done at autopsy. Another reason for the paucity of information on human CM pathogenesis is that human CM occurs almost exclusively in low-and middle-income countries. The resources in these countries for investigating CM pathogenesis are severely limited, and the resources provided by wealthier countries for such studies in malaria endemic areas have to date been relatively meager. Despite these limitations, in addition to cultural problems with acceptance of autopsies in children who die of CM, remarkable human brain autopsy studies have been con...

Endothelial Cells Potentiate Interferon-γ Production in a Novel Tripartite Culture Model of Human Cerebral Malaria

“…Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum malaria infection with an average mortality rate of around 20% even when treated with anti-malarial drugs [1], [2]. Despite decades of study, a detailed understanding of the causative mechanisms in CM has so far not been achieved.…”

Mouse NC/Jic strain provides novel insights into host genetic factors for malaria research

“…Microarray analyses have been performed on brain tissues from CM-susceptible (C57BL/6, CBA) and CM-resistant (BALB/c, DBA/2) mouse strains after P. berghei ANKA infection [13, 14, 52, 53, 72]. These analyses revealed that interferon (IFN) and IFN-regulating processes play a major role in experimental CM pathogenesis [13, 14, 42, 72]. Furthermore, it has been suggested that the C57BL/6 and CBA strains, which are predisposed towards Th1 immune responses, are susceptible to experimental CM, whereas BALB/c, which is predisposed toward Th2 responses, is resistant [28, 29].…”