Plasmodium malariae showed a pronounced preference for young red blood cells in human clinical isolates, and the parasite was also detected in bone-marrow cells in a humanized mouse model. Together, the findings point to young reticulocytes and bone marrow as sites worth examining when studying where this parasite is found.
The study combined ex vivo flow-cytometric profiling of P. malariae isolates with infection studies in a humanized mouse model. Clinical isolate analyses included four P. malariae samples, three uninfected blood samples, 10 P. falciparum isolates and three P. vivax isolates. The animal work tested whether P. malariae could be detected in human erythroid cells in bone marrow.
Young cells carried the stronger signal
In the human-isolate analysis, the researchers identified young red cells by looking for CD71, a marker used to distinguish reticulocytes from mature red blood cells. They stained the cells and used flow cytometry, a method that counts cells according to their markers and other signals, collecting at least 1 million measurements for stained samples. The reported result was a pronounced preference of P. malariae blood stages for CD71-positive reticulocytes over mature red blood cells.
The reported ratios varied across malaria species. For P. vivax, the mean ratio of infected CD71-positive reticulocytes to infected mature red cells was 93.5 ± 51.1, compared with 4.34 ± 4.03 for the P. falciparum comparison, described as about 18-fold higher. For P. malariae, the reported mean was 27.7 ± 5.81 versus 14.34 ± 4.03 for the P. falciparum comparison, described as fivefold higher and threefold lower than P. vivax. The same analysis contains conflicting P. falciparum comparator values, so these figures are best read as reported comparisons rather than a clean ranking.
Because CD71 is lost as reticulocytes mature, the researchers used a model to adjust the observed ratios for cell maturation and for the different erythrocytic cycles of the parasites, two days for P. vivax and three days for P. malariae. At the marked point in the analysis, the corrected relative preference was approximately 1.24 when the mean CD71 lifetime was assumed to be one day, with a half-life of about 17 hours. Across assumed half-lives from 0.5 to 1.6 days, the estimate stayed below the uncorrected ratio of 3.4.
The cell findings were not limited to the earliest parasite forms. Donor blood containing P. malariae showed all asexual blood stages and gametocytes, with trophozoites predominant, and high Hoechst signal was also seen in CD71-positive red cells. Hoechst intensity is an indirect marker of parasite replication or stage in this analysis, so it does not by itself establish how many cells had reached a particular stage.
The marrow signal came from mice
To examine the marrow, the researchers used HIS-HEry mice, which were reconstituted by injecting human CD34-positive cells into 3- to 4-day-old immunodeficient neonates. Human erythroid cells made up 7% to 40% of the mice’s bone-marrow cells, and 35% to 74% of those erythroid cells were CD71-positive. The mice then received 2.5 million to 5 million P. malariae-infected red blood cells, with blood and bone marrow collected nine days later.
Among nine infected mice, P. malariae was detected in the bone marrow of all nine and in the blood of eight. The mean parasite signal was higher in bone marrow, at 196.06 ± 181.52 copies per 100,000 human CD235a-positive cells, than in blood, at 37.01 ± 79.02 copies per 100,000 cells. The reported difference was not statistically significant, so the result indicates a pattern of greater marrow detection rather than a definitive difference in burden.
Imaging flow cytometry, which combines cell measurements with pictures of individual cells, identified infected immature bone-marrow red cells marked by CD71. Tests on sorted bone-marrow cells also detected P. malariae-specific 18S ribosomal RNA in both the CD71-positive and CD71-negative red-cell fractions. Together, those findings support marrow localization and infection of immature cells in this mouse model.
The boundary of the evidence
The evidence has important limits. The clinical-isolate analysis was small, with four P. malariae isolates and small comparator groups. The marrow result came from humanized mice rather than direct human bone-marrow samples, and the mouse experiment was sampled at day 9 after infection. The corrected reticulocyte estimate also depends on a kinetic model and the assumed CD71 half-life.
Taken together, the study supports a link between P. malariae and young red cells in the human isolates, plus marrow localization and infection of immature cells in this mouse model. It does not establish bone-marrow infection in human patients, because no direct human marrow evidence was provided.
Paper data and sources
Original title: Tropism offor young red blood cells and the bone marrow.
Authors: Barbara Mouyama, Vivienne Fey, Dorenda J A Schoorl et al.
Journal/Repository: Emerging microbes & infections
Status: Peer-reviewed
First online: 2026-10-07
DOI: 10.1080/22221751.2026.2731507
Original paper · Full text