Murine models of cerebral malaria: A qualified defence

Abstract

Cerebral malaria (CM) IS the most profound manifestation of severe malana in humans, arislng from PlasmodIum falciparum infection. presenting as an acute encephalopathy, and accompanied by various neurological sequelae including coma. The pathophyslology of this syndrome IS not fully understood and, recently, has been the subject of an animated debate’ 4. As the underlying cause of the symptoms of CM, the two proposed mechanisms (I) erythrocyte sequestration and mechanical blockage2 and (2) cytokine InductIon currently both have support. In the past, fundamental studies to examine the pathogenesis of human CM have often utilized the accesslblllty of, and ease of manipulation and Intervention afforded by, rodent malaria Infections in laboratory mice. The relevance of these models is. however, now being called Into question2,‘. Although a number of murlne models of severe malaria are available, few bear valid comparison with P halopar-urn CM on the basis of all current parasitological, morphologlcal and molecular criteria. Most notably, there IS no host-parasite combination in which the massive cerebra sequestration of etythrocytes observed in the human condition is accurately reproduced. That said, they have highlighted the Importance of the immune system in modulation of cerebral pathology. Plosmodrum berghei ANKA infection of CBA/Ca mice, for instance, IS a model In which stnklng cerebral complications develop, causing so-called ‘munne CM’. Manlfestatlons shared with its human counterpart include the onset of a reversible coma, severe neurological dysfunction and dlffuse cerebra microvascular abnormalriles. As parasitized erythrocytes of P. berghei ANKA lntnnsically lack the ability to cytoadhere, this form of cerebra disease IS notable for the fact that there IS an absence of parasite sequestration. However, there is an amplification of expression of cytoadherence receptors in cerebral capillaries which leads to a substantial sequestration of leukocytes. With this model, It has been shown that excessive productIon of tumour necrosis factor ol (TNF-a) IS a key factor In the pathogenesls of murine CM. Treatment of P berghe/-Infected mice A.W. Taylor-Robinson