Origin of recurrent Plasmodium vivax malaria – a new theory
To the Editor: The phenomenon of long-term relapse is familiar to many persons who have contracted malaria, and to their doctors. Attacks of Plasmodium vivax malaria (so-called benign tertian malaria) in particular can occur after symptomatic illness has been absent in the patient for months or years. Recurrent clinical P. vivax manifestations have been thought to originate from a dormant liver form, the discovery of which1 has become recognised as a classic landmark in the history of parasitology and tropical medicine. I correctly predicted the existence of the stage concerned (extrapolating from my rodent-associated research while a PhD student at Imperial College London) and coined the term ‘hypnozoite’ for it.2 For the past three decades, medical students worldwide have been taught that hypnozoites give rise to malarial relapse. However, new findings indicate that there might well be a second cause of recurrent P. vivax malaria.
Parasites responsible for recurrence of benign tertian malaria are frequently genotypically different (determined by molecular techniques) from those that gave rise to the initial symptomatic bout of disease. In other cases, parasites are genetically similar.3 , 4 The genotypes of sporozoites in inocula that are injected into the skin by mosquitoes are known to be diverse. Assuming that hypnozoites are directly sporozoite-derived (which they appear to be5 ), and that re-infection of any given patient has not taken place, the former (heterologous parasite) situation is therefore perfectly compatible with the hypnozoite concept of relapse.
I now suggest that there is a possible non-hypnozoite basis for the other (i.e. homologous parasite) phenomenon in at least some instances. Rodent malarial stages that might become latent for extended periods have recently been detected in splenic dendritic cells. These parasites are able to infect erythrocytes, and similar forms could be responsible for clinical human malaria that follows splenectomy for splenic trauma.6 Plasmodial stages like those in rodents will obviously now be searched for in dendritic cells from human spleens. I speculate that such forms or other merozoites may also be the source of recurrent P. vivax episodes which are conventionally always ascribed to homologous hypnozoite activation. If a recurrent clinical P. vivax attack can indeed be the result of renewed asexual reproduction of merozoites following a period of dormancy, as I hypothesise, then this would explain why parasites isolated from peripheral blood samples in recurrent malaria have sometimes proved to be genetically similar to those that were responsible for the primary clinical infection.
It is easier to appreciate the feasibility of this straightforward explanation than to imagine what the mechanistic basis of a homologous hypnozoite relapse postulation for renewed parasitaemia might be. The latter nevertheless remains a possibility. However, why some sporozoites of a particular genotype would multiply in the liver early in the infection, whereas others that are genetically homologous would form hypnozoites, is a great malariological mystery! How frequently are these two different paths followed concomitantly by genotypically homologous sporozoites? Or does this never, in fact, happen after all?
University of the Witwatersrand
1. Krotoski WA, Collins WE, Bray RS, et al. Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection. Am J Trop Med Hyg 1982;31:1291-1293.
2. Markus MB. Malaria: origin of the term hypnozoite. J Hist Biol (in press). http://dx.doi.org/10.1007/s10739-010-9239-3 (accessed 24 August 2011).
3. Chen N, Auliff A, Rieckmann K, Gatton M, Cheng Q. Relapses of Plasmodium vivax infection result from clonal hypnozoites activated at predetermined intervals. J Infect Dis 2007;195:934-941.
4. Imwong M, Snounou G, Pukrittayakamee S, et al. Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis 2007;195:927-933.
5. Markus MB. The hypnozoite concept, with particular reference to malaria. Parasitol Res 2011;108:247-252.
6. Wykes MN, Kay JG, Manderson A, et al. Rodent blood-stage Plasmodium survive in dendritic cells that infect naive mice. Proc Natl Acad Sci USA 2011;108:11205-11210.
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