Lessons from sickle cell disease in the treatment and control of malaria

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Lessons from Sickle Cell Disease in the Treatment and Control of Malaria
Philip J. Rosenthal, M.D. Malaria, especially infection with Plasmodium falciparum, has exerted strong selective pressure on the human genome. In a well-characterized, balanced polymorphism, persons who are homozygousfor the sickle hemoglobin mutation (in which valine replaces glutamic acid at position 6 in the β-globin chain of hemoglobin A, producing hemoglobin S) have serious hematologic illness, but those who are heterozygous for the mutation (and have hemoglobin AS) are asymptomatic and relatively protected against severe falciparum malaria as compared with those who have normal hemoglobin.1 A recentstudy by Ferreira and colleagues2 offers an improved understanding of how hemoglobin AS protects against malaria, thereby providing insight into potential means of treating and controlling this disease. The consequences of infection with P. falciparum range from asymptomatic parasitemia to severe and often fatal malaria. Repeated malaria infections lead to gradual acquisition of immunity in regionswhere it is endemic, but the mechanisms of antimalarial immunity remain poorly understood. In addition, the reasons why some infections progress from asymptomatic parasitemia to uncomplicated febrile illness and others to severe clinical manifestations are unclear. Ferreira and colleagues used a well-established animal model of sickle cell disease — in which mice express human β-globin with thesickle mutation and two additional mutations — to gain insight into the mechanisms of antimalarial protection in persons with hemoglobin AS.2 The researchers infected the mice with the rodent parasite Plasmodium berghei, which can cause a severe illness with features similar to those of human cerebral malaria, one of the most serious manifestations of human infection with P. falciparum. As seen inprior studies, when the mice were infected with P. berghei, those with the sickle cell mutation had a significantly lower incidence of cerebral malaria than did wild-type mice. Ferreira and colleagues suggested that the mechanism of protection in the mice with the sickle cell mutation was tolerance rather than resistance, since the mice acquired the same density of parasites as did wild-type micebut were nonetheless protected against cerebral malaria. This protection followed the induction of expression of heme oxygenase-1, an enzyme that breaks down free heme. The accumulation of free heme was thereby prevented, limiting the severity of malaria. This new study has limitations in its ability to teach us about the mechanism of protection against malaria in people with hemoglobin AS. First,the transgenic mice studied offer but a crude model of the disease in humans, particularly in terms of the nature of the protection offered by hemoglobin AS against severe malaria. Second, the illness caused by infection with P. berghei in mice differs from that caused by infection with P. falciparum in humans; the application of findings from the study of P. berghei in mice to human cerebralmalaria is controversial.3 Third, the effects of the sickle mutation in mice may not fully represent those seen in humans with hemoglobin AS; in mice, protection against cerebral malaria was not accompanied by decreased parasite loads, whereas in most studies of humans, persons with hemoglobin AS who present with symptomatic malaria have lower parasite loads than those with normal hemoglobin (Fig. 1).1These limitations notwithstanding, the study by Ferreira and colleagues offers food for thought about the treatment and control of malaria. With regard to the treatment of severe malaria, pharmacologic stimulation of the pro-

n engl j med 364;26

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june 30, 2011

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