Species-Specific Inhibition of Cerebral Malaria in Mice Coinfected with Plasmodium spp.

Recent observations in Africa (6), Asia (14), and Oceania (50) have suggested that associations between different malaria parasite species might actually have a beneficial influence on the clinical activity of Plasmodium falciparum infections, the major cause of malaria mortality in humans. This notion has been reinforced through detailed longitudinal observations in Thailand (44), where the simultaneous presence of P. vivax in patients presenting with P. falciparum was observed to reduce the risk of developing severe disease or complication (25), treatment failure (33), and anemia during follow-up (34). The epidemiological and clinical relevance of interactions between parasite species found in the same host, derives from the emerging realization that mixed-species infections are a common feature of malaria in humans. Three of the parasite species—P. falciparum, P. vivax, and P. malariae-to which humans are susceptible are globally distributed, although P. vivax is rare in West Africa. A fourth species, P. ovale, is predominantly found in West Africa but has not been recorded in the Americas. Residents in most areas of endemicity for malaria are subjected to infection by two, and often three, Plasmodium species. Scrutiny of the early epidemiological records revealed that mixed-species infections were generally found significantly less frequently than expected (21), a pattern common to past and present surveys where parasite detection is achieved through microscopic examination. The development (43) and subsequent use of sensitive PCR-based species detection methods has clearly established that mixed Plasmodium species infections are actually very common (28, 42), even in areas of relatively low endemicity (32, 39). Given that in many areas of endemicity mixed-species infections are likely to be the rule rather than the exception, it is important to investigate whether interactions between Plasmodium species have any consequences on the pathological evolution of the infections. Detailed investigations of the influence of mixed infections on pathology and elucidation of underlying mechanisms are best undertaken through carefully controlled experimental infections that can only be envisaged in animal models. Cost, ethical considerations, and the dearth of immunological reagents preclude primates as initial experimental models for such investigations. Laboratory rodents, though imperfect models for the human infection, offer the most practical alternative, in particular through the availability of cloned lines from different Plasmodium species to which they are susceptible. Laboratory mice infected with the P. berghei ANKA cloned line (PbA) provide a suitable experimental model for the investigations of the pathogenesis of cerebral malaria (CM) (23). PbA-infected susceptible mice develop overt clinical signs between day 6 (D6) and D9 and die within 48 h of that onset. The development of CM in mice was recently shown to be associated with the migration of pathogenic CD8+ T cells to the brain, a mechanism thought to be initiated by PbA parasite sequestration in the brains of the CM-susceptible mice (5, 15). We report here the first detailed study of the influence of mixed-species infections on the expression of PbA-induced CM. Infection by PbA was combined with one of five different parasite lines, from the same or different species, chosen for their inability to induce CM in the mice used.