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Parasite Origins of Long-term Malarial Recurrences

May 28, 2020 - 00:10 -- Miles Markus

As is well known, long-term malarial recurrences are a feature of human infections caused by species of Plasmodium. The frequency of recurrence varies. In P. falciparum malaria, long-term recurrence is rare, but not (contrary to popular belief) non-existent. P. malariae [Pm] and P. vivax [Pv] only will be considered below; and with reference to only the bone marrow as a site of parasite occurrence.

It has been known from individual cases of malaria that both Pm and Pv can be present in the bone marrow. Experimental work has in the meantime shown that Pv is, in fact, highly prevalent in bone marrow [see the first reference below]. Both species are "famous" for causing long-term malarial recurrences. As regards homologous long-term recurrences, it has generally been thought in the past that the origin is circulating blood-stage parasites of Pm; but hypnozoites of Pv. The former assumption has been based partly on minimal evidence that hypnozoites apparently do not occur in the life cycle of Pm. This aside, Pm infections are as persistent after blood-stage parasite inoculation as they are following sporozoite-transmitted Pm malaria. Even if hypnozoites do occur in the life cycle of Pm, long-term Pm recurrences in blood-stage-initiated malaria cannot be hypnozoite-mediated. It is biologically impossible, because hypnozoites are directly sporozoite-derived; and there are no sporozoites in post-passage, blood-stage Pm inocula.

TWO QUESTIONS are (this might not be immediately comprehensible, i.e. upon first reading):

(A) Given that the same non-hypnozoite parasite forms which occur in blood-stage-initiated Pv malaria are likely to occur in sporozoite-transmitted Pv malaria as well, can at least some LONG-TERM HOMOLOGOUS Pv malarial recurrences in sporozoite-initiated Pv infections have a NON-HYPNOZOITE parasite origin analogous to the non-hypnozoite parasite origin of long-term recurrences in blood-stage-induced Pm malaria?

(B) Can a non-circulating parasite source of recurrences be bone marrow (for example) in both the Pm and Pv hypnozoite-independent recurrence scenarios outlined here?

See the 2nd to 5th references below for combined elucidatory Pm extrapolative discussion in relation to Pv malarial recurrences.

 

REFERENCES

"Plasmodium asexual growth and sexual development in the haematopoietic niche of the host" https://doi.org/10.1038/s41579-019-0306-2

"Malaria eradication and the hidden parasite reservoir" https://doi.org/10.1016/j.pt.2017.03.002

"Biological concepts in recurrent Plasmodium vivax malaria" https://doi.org/10.1017/S003118201800032X

"Do hypnozoites cause relapse in malaria?" https://doi.org/10.1016/j.pt.2015.02.003

"Dormancy in mammalian malaria" https://doi.org/10.1016/j.pt.2011.10.005

Comments

Submitted by Miles Markus on

There is, of course, compelling evidence that hypnozoites are a source of long-term recurrences of P. vivax malaria. But question "A" above is valid, nevertheless. Note the precise wording "at least some", for homologous long-term P. vivax recurrences. These do take place in the long term (not only in the early infection), as is documented in the literature.

Submitted by Miles Markus on

The decade-old, hypnozoite-independent Plasmodium vivax malarial recurrence idea that is the subject of the above Blog has just received – via the two very interesting papers listed below – what can be interpreted as additional and significant support.

The two articles are concerned with the spleen. The subject of the spleen arose in a couple of the publications listed at the end of the Blog. But, most importantly, also in this one (although the spleen is not mentioned in its abstract):

https://doi.org/10.1016/j.pt.2018.08.010

For the hypnozoite-independent recurrence concept in a nutshell, see opposite the year 2011 in the Table that the link below brings up (I have copied the link from the previous Comment that was posted re the Blog):

https://www.semanticscholar.org/paper/Biological-concepts-in-recurrent-Plasmodium-vivax-Markus/03c84f86a951b605fe389843b14dea4b84329d3f/figure/0

The two hot-off-the-press papers referred to above are:

Fernandez-Beccera, C. et al. 2020. Plasmodium vivax spleen-dependent genes encode antigens associated with cytoadhesion and clinical protection. PNAS, in press (published online May 21).

Toda, H. et al. 2020. Plasma-derived extracellular vesicles from Plasmodium vivax patients signal spleen fibroblasts via NF-kB facilitating parasite cytoadherence. Nat. Commun. 11: 2761 (published online 2 June).