Home Sweet Home: Plasmodium vivax-Infected Reticulocytes-The Younger the Better?

Richard Thomson-Luque,José M Bautista

doi:10.3389/fcimb.2021.675156

Abstract

After a century of constant failure to produce an in vitro culture of the most widespread human malaria parasite Plasmodium vivax, recent advances have highlighted the difficulties to provide this parasite with a healthy host cell to invade, develop, and multiply under in vitro conditions. The actual level of understanding of the heterogeneous populations of cells—framed under the name ‘reticulocytes’—and, importantly, their adequate in vitro progression from very immature reticulocytes to normocytes (mature erythrocytes) is far from complete. The volatility of its individual stability may suggest the reticulocyte as a delusory cell, particularly to be used for stable culture purposes. Yet, the recent relevance gained by a specific subset of highly immature reticulocytes has brought some hope. Very immature reticulocytes are characterized by a peculiar membrane harboring a plethora of molecules potentially involved in P. vivax invasion and by an intracellular complexity dynamically changing upon its quick maturation into normocytes. We analyze the potentialities offered by this youngest reticulocyte subsets as an ideal in vitro host cell for P. vivax.

Highlights

Plasmodium vivax (P. vivax) is the reigning malaria-causing parasite outside the African continent (Gallup and Sachs, 2001)
The possibility that some very immature DARC- reticulocytes in the bone marrow, and in peripheral blood (Thomson-Luque et al, 2018), harbor marginal expression of DARC tempts us to speculate that they may be the explanation behind the possibility of transmission between Duffy- individuals infected with P. vivax
More experimentation is clearly deserved on sustaining a parallel and healthy reticulocyte maturation of both its surface as well as internal components under in vitro conditions. Are both of these cytoplasmic and membrane maturations needed for P. vivax to develop inside? Is there a certain rate for a fine-tuned progression of P. vivax inside this delusory host cell? These are the key questions to be addressed; in order to gain more confidence in immature reticulocytes for achieving P. vivax culture in vitro, we must first discard that some of the described observations on the parasite’s biology are not just an artifact of non-viable reticulocytes in a non-optimized in vitro environment

Summary

INTRODUCTION

Plasmodium vivax (P. vivax) is the reigning malaria-causing parasite outside the African continent (Gallup and Sachs, 2001). The suggested dependency on CD71 for invasion has re-fueled the idea that a great proportion of P. vivax biomass resides in hematopoietic organs, such as the bone marrow (Baird, 2013) (and potentially the spleen, contributing to the final steps of reticulocyte maturation) (Rhodes et al, 2016; Toda et al, 2020) These are environments full of the younger CD71+ reticulocytes and, the homes of a subset of reticulocytes whose surfaces are extremely enriched in CD71: the CD71high reticulocytes. The possibility that some very immature DARC- reticulocytes in the bone marrow, and in peripheral blood (Thomson-Luque et al, 2018), harbor marginal expression of DARC tempts us to speculate that they may be the explanation behind the possibility of transmission between Duffy- individuals infected with P. vivax This is further supported if the molecules characteristic of reticulocyte immaturity that they carry have a role as alternative receptors/co-receptors. Aside from receptor molecules, other players constitutive of the immature reticulocyte membrane may need to be looked into and taken care of under in vitro conditions

A CONSTANT REMODELING OF THE RETICULOCYTE MEMBRANE IN VITRO IS NEEDED

DISCUSSION