Immature reticulocytes as preferential host cells and the challenges for in vitro culture of Plasmodium vivax

Invited commentary on ‘Plasmodium vivax: restricted tropism and rapid remodeling of CD71 positive reticulocytes’ by B. Malleret et al.

The interactions between Plasmodium vivax and the bone marrow have received considerable attention in recent years. First, John Kevin Baird recently suggested, in his extensive review of the pathogenesis of severe vivax malaria, that counting the number of Plasmodium vivax blood stages circulating in peripheral blood might not provide a reliable estimate of the total parasite biomass harbored by the host, since parasites also appear to ‘sequester’ in internal hematopoietic organs such as the bone marrow.¹ Moreover, red blood cells infected with mature forms of P. vivax (especially schizonts) have been shown to adhere at some extent to endothelial receptors and this ability correlates negatively with the abundance of schizont-infected red blood cells in the peripheral blood of vivax malaria patients.² Interestingly, the reticulocyte-prone rodent parasite P. yoelii (which mimics several biological features of P. vivax) has been reported to preferentially invade immature reticulocytes in the bone marrow and spleen of Balb/c mice.³

In the 19 February 2015 issue of Blood, Malleret and collaborators⁴ conclusively show that P. vivax isolated from Thailand preferentially invade in vitro very immature reticulocytes expressing high amounts of the transferrin receptor CD71 on their surface (CD71high and CD71med). They further hypothesise that merozoite invasion by P. vivax takes place predominantly in the bone marrow, a major reservoir of these very immature host cells.³

This preference of P. vivax for very immature reticulocytes opens several new questions. What proportion of the parasite's biomass is actually concentrated in the bone marrow? What are the main implications for the pathophysiology of vivax malaria? Can parasites hidden in the bone marrow escape from peripheral immune responses? What are the factors driving the migration of P. vivax free merozoites or schizont-infected reticulocytes from the sinusoidal capillary lumen to the primary hematopoietic sinus?

Malleret et al.⁵ further show that, although CD71+ reticulocytes are preferentially infected in vitro, most P. vivax infected red blood cells circulating in peripheral blood from patients in Thailand are in fact CD71-. They provide evidence that infection of CD71+ reticulocytes with P. vivax accelerates host cell remodeling and maturation. They documented a faster disappearance (up to six hours after merozoite invasion) of the inner trabeculae from P. vivax infected reticulocytes, compared with non-infected reticulocytes. Although most infected reticulocytes appear to mature and lack CD71 expression, it remains unclear how some mature asexual stages (trophozoites and schizonts) can still be found inside some CD71+ cells. Further work on the completion of maturation in vitro into healthy fully multi-nucleated P. vivax schizonts inside these different CD71+ subpopulations of reticulocytes remain to be performed.

These data suggest that in vitro culture for P. vivax may require the use of immature CD71+ reticulocytes which represent an extra challenge for its development, as the sources for obtaining high amounts of these cells would need to be determined. Furthermore, it indicates that a large proportion of the P. vivax biomass could be found in recondite places such as the bone marrow, with clear implications for malaria diagnosis.

Acknowledgements

KKGS thank CAPES (Coordenação de Pessoal de Nível Superior-Brazil) for scholarship (#1792-14-8).

Disclaimer Statements

Contributors RTL and KKGS contributed equally to this work. Both analysed and wrote the manuscript.

Funding None.

Conflicts of interest The authors declare that they have no conflict of interest.

Ethical approval Not applicable.