The hypnozoite and malarial relapse.

As described above, perhaps the most compelling arguments against the cyclic schizogony (Shortt-Garnham) hypothesis of malarial relapse have been (1) its inability to explain the disparate relapse patterns of P. vivax strains as they occur in nature, and (2) the dearth of concrete evidence for its support. The hypnozoite theory, in contrast, both provides an explanation for the variety of observed relapse patterns, and has direct morphologic and time-related, quantitative evidence for its support. Moreover, it provides a potential, unifying framework for the development of relapsing malaria from the time of introduction of sporozoites onward, taking as controlling factors, both the survival of the parasite and ecological interactions within its natural environment. It also suggests the possibility of an improved taxonomic classification, one based on whether or not the hypnozoite stage exists in a given species. Finally, Figure 6 presents a composite of relapse data pertinent to a number of strain groups of P. vivax, in comparison with a generalized, nonrelapsing species, schematically depicted within the framework of the hypnozoite theory. Thus, no hypnozoites are shown to result from sporozoites of the nonrelapsing species at one extreme, whereas no sporozoites undergoing immediate schizogony (i.e. without dormancy) are found at the other, the "lost" P. vivax strain of Nicolaiev. In between, varying proportions of sporozoites are depicted as producing hypnozoites, which exhibit varying periods of dormancy, ranging from less than 1 month (within the wide complement of the "tropical" strains) to approximately 21 months or more for the "northern" strains, before activation to schizogony and resultant relapse at the observed intervals. Although the actual proportions of each sporozoite/hypnozoite type within the strains depicted are unknown, a single, successful sporozoite can yield a parasitemic relapse--their distribution among the major strain groupings appears reasonably distinct, and, to some extent, defines each grouping. The sequences of sporozoite to pre-erythrocytic schizont, to merozoite release, to erythrocyte, as seen in nonrelapsing malarias and early primary parasitemias, versus sporozoite to hypnozoite, to pre-erythrocytic schizont, to erythrocyte, as seen in relapses, are easily inferred from this summary of observed relapses. It is difficult to see how these observed phenomena can be satisfactorily explained by a cyclic schizogony mechanism. It must be emphasized, nevertheless, that additional work with other relapsing and nonrelapsing species is necessary in order to establish the concept fully, and to determine the molecular mechanisms for dormancy and activation of hypnozoites.(ABSTRACT TRUNCATED AT 400 WORDS)