Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak.

Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.

Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

Low incidence of the severe complications of malaria and absence of malaria-specific mortality, in Tensa, Sundergarh district, Orissa state, India, an area hyper-endemic for malaria.

The incidence of severe malaria and malaria-specific mortality were investigated in a hospital, for miners and their families, at Tensa in the Sundergarh district of Orissa state in India. Tensa lies in area where malaria (predominantly caused by Plasmodium falciparum) is hyper-endemic. The hospital records for 1995--1999 showed that, although annual admissions for malaria increased over the study period, there were very few admissions for severe, complicated malaria and no reports of malaria-specific deaths. Most of the patients who had been admitted with cerebral malaria either came from areas around but not within the town of Tensa or were recent arrivals in the town. It appears that the outcome of malaria is influenced not only by the intensity of local transmission (which affects the immunological status of the human hosts) but also by social factors such as the education and health-seeking behaviour of the local population and the health-care facilities available. The low incidence of severe malaria observed in Tensa was probably the result of patients presenting early in the course of their illness and taking antimalarial treatment, iron supplementation and supportive therapy at the appropriate times.