In this issue of Blood, Malleret and colleagues show the importance of the bone marrow in Plasmodium vivax biology by proving the preferential infection of young reticulocytes (generally restricted to the bone marrow), which then experience accelerated maturation postinvasion.1 

Proposed model for P vivax development in the bone marrow. (A) P vivax infects stage III reticulocytes that have egressed by diapedesis to the sinusoidal capillary lumen. Alternatively, P vivax merozoites or P vivax–infected erythrocytes might enter the red bone marrow compartment, leading to invasion of CD71+ reticulocytes. Accelerated reticulocyte aging increases host cell deformability for subsequent endothelial crossing toward blood circulation. Adapted from Figure 5 in the article by Malleret et al that begins on page 1314. (B) Proposed model for P falciparum development in the bone marrow. Presence of immature gametocytes in the bone marrow extravascular space may be explained by erythrocytes infected by stage I gametocytes or sexually committed ring stages entering the bone marrow stroma through the endothelial lining. Alternatively, asexual schizonts, which develop in the extravascular compartment, may produce sexually committed merozoites that invade erythroid precursors, whose remodeling may share possible similarities with that of P vivax. Mature gametocyte-infected host cells cross the endothelial barrier to reenter the circulation. Adapted from supplemental Figure 7 in Joice et al.7  Professional illustration by Patrick Lane, ScEYEnce Studios.

Proposed model for P vivax development in the bone marrow. (A) P vivax infects stage III reticulocytes that have egressed by diapedesis to the sinusoidal capillary lumen. Alternatively, P vivax merozoites or P vivax–infected erythrocytes might enter the red bone marrow compartment, leading to invasion of CD71+ reticulocytes. Accelerated reticulocyte aging increases host cell deformability for subsequent endothelial crossing toward blood circulation. Adapted from Figure 5 in the article by Malleret et al that begins on page 1314. (B) Proposed model for P falciparum development in the bone marrow. Presence of immature gametocytes in the bone marrow extravascular space may be explained by erythrocytes infected by stage I gametocytes or sexually committed ring stages entering the bone marrow stroma through the endothelial lining. Alternatively, asexual schizonts, which develop in the extravascular compartment, may produce sexually committed merozoites that invade erythroid precursors, whose remodeling may share possible similarities with that of P vivax. Mature gametocyte-infected host cells cross the endothelial barrier to reenter the circulation. Adapted from supplemental Figure 7 in Joice et al.7  Professional illustration by Patrick Lane, ScEYEnce Studios.

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Plasmodium vivax mainly invades reticulocytes, a heterogeneous population of red blood cell precursors characterized by a reticular network of residual RNA, whose maturation is indicated by the decreasing expression of the transferrin receptor CD71. This host cell specificity shapes P vivax pathobiology, and the strict requirement for reticulocytes has hampered the establishment of an in vitro culture system for this parasite. By sorting different developmental stages of cord blood reticulocytes for use in an ex vivo invasion assay, Malleret and colleagues show that P vivax merozoites prefer the youngest of the young erythrocytes. The immature CD71+ reticulocytes, generally restricted to bone marrow, were more efficiently invaded than older CD71 reticulocytes principally found in peripheral blood. This finding was puzzling, because P vivax ring-stage parasites from patients were instead predominantly found in CD71 reticulocytes. Analyzing the first steps of P vivax invasion of CD71+ reticulocytes, Malleret and colleagues revealed a remarkably rapid remodeling of P vivax–invaded reticulocytes, leading to increased deformability, accelerated loss of CD71, and replacement of clathrin pits by distinctive caveolae nanostructures.

The narrow tropism toward CD71+ immature reticulocytes, produced and largely residing in the bone marrow,2  raises the intriguing possibility that P vivax invasion may mainly take place in this organ rather than in the circulating blood. The authors accordingly suggest that increased deformability associated with the accelerated reticulocyte aging might contribute to the trafficking of mature parasites into this organ and the egress of infected reticulocytes into the peripheral blood system. As pointed out in the article, the accumulation of P vivax infections in the bone marrow extravascular spaces may explain early observations of patients scored negative for P vivax in peripheral blood but positive in bone marrow biopsy specimens.3  Several case reports described recurrences of P vivax, as well as Plasmodium falciparum, after bone marrow transplants.4  Together with the evidence provided by Malleret and colleagues, these observations suggest that bone marrow can be a site where P vivax parasites may hide and develop.

Recent reports have placed the host-parasite interplay in the bone marrow at the center of pathophysiology and transmissibility of the other main human parasite P falciparum by demonstrating the enrichment of late parasite stages and immature gametocytes in this organ, with the latter readily found in the bone marrow extravascular compartment.5-7  The current study shows the potential of the bone marrow as a niche where P vivax invasion can occur before reentering the circulation (see figure). Intriguing similarities may deserve further attention. Most of the erythroid precursors containing P falciparum immature gametocytes in the marrow stroma in autopsy specimens were CD71,7  suggesting a similar parasite-mediated acceleration of host cell differentiation. Moreover, the rapid increase in deformability of the P vivax–infected immature reticulocytes, proposed to facilitate migration through the bone marrow sinusoidal lining, parallels the analogous reduction in the rigidity of erythrocytes infected with P falciparum mature sexual stages, which may help their release from the bone marrow sequestration sites to peripheral circulation.8 

The study by Malleret and colleagues raises several questions with far-reaching implications for P vivax biology that may have clinical impact. First, what is the role of bone marrow as a reservoir of P vivax parasites and what are the implications for strategies to eliminate malaria? The bone marrow is emerging as a site where both P vivax and P falciparum can hide and sustain infection and transmission, posing new challenges for malaria elimination initiatives directed at identifying and treating all Plasmodium infections. Second, through which mechanisms do infected reticulocytes transverse the bone marrow sinusoidal capillaries to the primary hematopoietic sinus? The authors argue that only young reticulocytes that have migrated out of the red bone marrow would be available for P vivax invasion, unless invasion principally occurs in the extravascular space of the red bone marrow. The latter scenario would imply a 2-way journey of P vivax merozoites and freshly invaded reticulocytes through the bone marrow sinusoidal capillaries, similarly to what has been proposed for P falciparum.7  Third, to what extent are anemia or inflammatory reactions—common during P vivax infection—triggered by the presence of malaria parasites in the bone marrow, and might they disrupt the sinusoidal lining, permitting cellular transit? A relationship has been suggested between hematologic disturbances and P falciparum development in bone marrow,5  which raises further questions on how this interplay in bone marrow is modified in the 2 parasite species after clinical malaria ceases in asymptomatic infected individuals, because these will stand as the last, most challenging parasite reservoirs to be attacked to achieve malaria eradication. Fourth, how does P vivax accelerate reticulocyte aging? Do loss of the CD71 clathrin pits and the formation of microvesicles contribute to the rapid host cell remodeling, and are there common mechanisms to affect deformability of reticulocytes by P vivax and of erythrocytes by P falciparum gametocytes?8  Finally, do parasites in the bone marrow reach some degree of refractoriness to treatment, as shown for Salmonella typhi,9  malignant hematopoietic cells, and epithelial tumor cells that metastasize to bone?10  Investigating these topics will allow us to begin to dissect the role of bone marrow in the P vivax biology and the manifestation of disease.

Bone marrow, which accounts for approximately 5% of the body weight in humans, generates all hematopoietic cells circulating in peripheral blood. Although functional alterations of the bone marrow under pathogen attacks are largely unknown, it is tempting to speculate that even small changes in this delicate environment may lead to significant modification in the cellular constituents in peripheral blood and tissues. An important role for bone marrow is emerging in the pathobiology of P falciparum malaria. Malleret and colleagues expand a possibly similar role in P vivax, requiring the assessment of how this organ contributes to the parasite biomass and the pathogenesis in this parasite. As for P falciparum,7  investigations of postmortem samples from P vivax malaria cases would be of great value.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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