Spotlight New Evidence for Hypnozoite- Independent Plasmodium vivax Malarial Recurrences Miles B. Markus 1,2, * Information provided in recent, related papers has wide-ranging implications concerning, inter alia, the transmission of malaria, drug treatment, and eradication of the disease. Additionally, the research results represent support for the idea that recurrences of Plasmo- dium vivax malaria can arise from both liver hypnozoites and extra- vascular merozoites in bone marrow. The most practically significant advances in knowledge concerning the life cycle of mammalian Plasmodium that have taken place since the hypnozoite was discov- ered four decades ago (see Table 1 in [1]) were published in 2018. Some implica- tions of this research are discussed here, with particular emphasis on how current dogma surrounding the origin of malarial relapse is affected. Firstly, Obaldia et al. [2] found that bone marrow and the liver of splenectomized Aotus and Saimiri monkeys are important tissue reservoirs of blood-stage P. vivax parasites. On the basis of their investiga- tions, the authors estimated that approxi- mately 30% of the total parasite load was concealed there, mainly extravascularly. They speculated that localization of para- sites to a reservoir in bone marrow might be part of the explanation as to why many P. vivax infections in Africa have been overlooked. The P. vivax parasite distribution pattern in spleen-intact humans and monkeys remains to be determined. Secondly, it has been shown that Plas- modium berghei parasites accumulate extravascularly in the reticuloendothelial system of laboratory mice, where cryptic cycles of asexual reproduction take place [3,4]. Extravascular parasites may be a source of recrudescence in both murine and primate malaria [4]. This conclusion amounts to indirect endorsement of a previous assertion, namely, that homolo- gous P. vivax malarial recurrences prob- ably (with unknown frequency) have a hypnozoite-independent, extravascular bone marrow or splenic origin [1,5]. It has also been pointed out [4] that ongoing multiplication of parasites in hematopoi- etic tissues might be a mechanism whereby transmission of human malaria is facilitated in regions where the disease is seasonal. Following the elucidation, outlined above, of aspects of parasitological involvement of the spleen in mammalian malaria [3,4], it is worth reflecting upon the phenomenon of recurrence in sple- nectomized humans. Such individuals have enhanced susceptibility to plasmo- dial infection; and in a recent study, it was found that the risk of presenting with postsplenectomy clinical P. vivax malaria was greater than for Plasmodium falci- parum malaria [6]. Why there should be this difference is not known. That aside, one possible explanation for postsple- nectomy, non-reinfection, human malar- ial recurrence is that parasites which had accumulated in or were cycling in the spleen are displaced from extravascular splenic tissue [3,4,6] and gain entry to the bloodstream [6]. More hypothetically, another parasite source that could cause or contribute to recurrent human malaria in splenectomized individuals would per- haps be merozoites in dendritic cells, with recurrences likewise taking place as a result of traumatic disruption of splenic tissue integrity [7]. However, it is not yet known whether dendritic cells in the human spleen are parasitized by Plasmodium, as they can be in rodents [7]. The same argument applies in theory to merophores, which have so far only been detected in the life cycle of some rodent malaria parasites, especially in the spleen [8]. If, however, merophore for- mation is also a feature in human malaria, the bloodstream could obviously become seeded, following damage to the spleen, with numbers of parasites via splenic blood vessels. This route of entry of parasites into the peripheral cir- culation would already be a fait accompli by the time splenectomy is carried out. The role of immunity in relation to sple- nectomy is a different subject and is not discussed here. Considering how long it took before hyp- nozoites were recognized in the plasmo- dial life cycle, it seems unlikely that sufficient scrutiny of human spleens will yet have taken place, with merophores and malaria parasites in dendritic cells in mind, to exclude the possibility that such stages occur there. In section, these forms (if present) would need to be distin- guished from erythrocytic schizonts – which they might at first glance vaguely resemble at low magnification. The fact that erythrocytic parasites in mouse spleens were found to be less sensitive to artemisinin than those in the bloodstream, can be extrapolated to human malaria [4]. Another example of post-treatment persistence of parasites in the spleen is that of the aforementioned rodent plasmodial stages in plasmacytoid dendritic cells; viability was demonstrated after detectable peripheral parasitemia had been cleared by antimalarial drugs [7]. To give a third example of site-asso- ciated drug efficacy, it was revealed by TREPAR 1798 No. of Pages 2 Trends in Parasitology, Month Year, Vol. xx, No. yy 1