A model of how the sickle-cell gene produces malaria resistance

Abstract

A model of resistance to falciparum malaria provided by the sickle-cell gene in heterozygous state is presented based on earlier hypotheses, the life cycle of P. falciparum within its human host, and the nature of host response. Falciparum populations are reduced in size with each cycle of erythrocytic schizogony in sicklers because many parasitized cells are sequestered, sickled, and phagocytized within areas of low P02 following host vasoconstriction induced by antigen release during schizogony. Populations highly synchronous in their timing of schizogony grow more rapidly than asynchronous populations because a smaller proportion of their members will be trapped, sickled, and phagocytized following vasoconstriction. Differences in synchronicity of schizogony, combined with survival of early ring forms and differences between hosts in time of onset of vasoconstriction, can account for differences in the height of parasitemia between infected sicklers. The sickle-cell gene provides resistance only to falciparum malaria because other forms undergo schizogony in the peripheral circulation where P02 is too high to allow sickling, and/or their synchrony of schizogony is too great to allow a sufficient proportion of their infecting populations to be destroyed with each cycle of erythrocytic schizogony. Resistance to falciparum malaria based upon the sickle-cell gene is restricted to early childhood because internal organs atrophy consequent to successive sickling episodes brought on by febrile diseases, including falciparum malaria itself. The gradually acquired immunity of both non-sicklers and sicklers reduces the differences in resistance between them until sicklers enjoy no advantage in falciparum resistance. Ways of testing the model are considered.