TNFa in Cerebral Malaria

At the global level, malaria still represents a major health problem. It is a leading cause of morbidity, and its consequences, in terms of disability and mortality, oppress the poorest nations with devastating socioeconomic effects (40-42). Malaria is a parasitic disease caused by protozoa of the genus Plasmodium. Cerebral malaria (CM) is a common clinical expression of P. falciparum infection, especially among children, and a primary cause of death. CM is lethal if untreated, and even when treated, it frequently results in mortality (43). CM pathogenesis remains largely unknown, but it has been clear for a while that it largely depends on the inflammatory host reaction to the parasite, encompassing TNF production (44). In simplified terms, sequestration of blood cells, including parasitized red blood cells (pRBC), in the brain capillaries, critically favored by proinflammatory cytokines, would result in CM via blood flow obstruction and ischemia (45).

The evidence for TNF involvement in human CM is abundant but circumstantial in nature. A number of studies have shown that high levels of circulating TNF are a hallmark of CM and correlate with manifestations of disease severity such as depth of coma, multiple organ dysfunction, and mortality (46-51). These studies, however, have not documented a causative role for TNF in CM, even if one of them (50) showed that pentoxifylline, an inhibitor of TNF production (51), exerts beneficial effects on the course of CM in children. This effect is associated to a decline of TNF serum levels. However, the evidence for TNF involvement in experimental CM is unequivocal.

A few animal models of CM have been developed (53), but the one established by G. E. Grau et al. (54) in mice using P. berghei ANKA has been instrumental in demonstrating the contribution of the immune system and TNF to CM pathogenesis. This model results from the parenteral injection of P. berghei ANKA-pRBR into mice of susceptible strains, such as the CBA/Ca or the C57Bl/6. It consists of an acute syndrome dominated by neurological signs (paralysis, ataxia, convulsions) that arises 6-9 d after infection and is invariably lethal 12-36 h after onset. The injection of P. berghei ANKA-pRBR into mice of resistant strains, such as the BALB/c, does not result in any acute syndrome or early mortality, but in a state of chronic anemia that is lethal during the fourth week of infection. The finding that athymic nude mice are protected against CM initially suggested that the immune response is responsible for the development of CM (55). This hypothesis was then largely confirmed and expanded by a number of other findings, such as that T-cell depletion (56,57), cyclosporin A treatment (58), and the lack of IRF-1 (59) protect against CM.

Passive immunization experiments first pointed to TNF as an essential mediator in the pathogenesis of CM (60). These experiments involved the use of polyclonal anti-mouse TNF Ab, similarly to those that proved the relevance of TNF to endotoxin-induced lethality (61). Later experiments, involving the use of transgenic mice expressing a TNFR-I construct as a decoy reagent, confirmed the role of TNF in CM pathogenesis (62). Subsequent experiments using mice lacking either TNFR-I or TNFR-II showed that TNFR-II, but not TNFR-I, plays a critical role in CM pathogenesis, possibly because ICAM-1 upregulation on brain endothelium may occur in absence of TNFR-I but not TNFR-II (63). In fact, endothelial ICAM-1 seems to contribute to cell sequestration in brain capillaries by interacting with LFA-1 expressed on blood cells (64).

In conclusion, it is difficult to say how relevant the P. berghei ANKA model by Grau et al. is to human CM. P. falciparum-pRBCs show pathogenically important features that permit their binding to the endothelium. These features do not find counterparts in P. berghei-pRBCs (45). Thus, human CM is characterized by pRBC sequestration in brain capillaries, while experimental CM essentially by sequestration of leukocytes (54). Lesions of the brain capillary endothelium seem to occur similarly in the two conditions (54), however, making it reasonable to accept that at least to a certain extent, P. berghei ANKA infection of susceptible mice is a valid tool to deepen our knowledge of human CM.

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