Non-genetic red blood cell variability can modulate hemoglobin consumption by intracellular Plasmodium falciparum

ABSTRACT Natural, non-genetic variation among host cells can shape infection outcomes, yet its role in intracellular parasite dynamics remains poorly understood. Here, we show that variability in hemoglobin (Hb) content among individual red blood cells (RBCs) modulates nutrient consumption by Plasmodium falciparum , the most lethal malaria parasite. Using label-free quantitative-phase imaging (QPI), we measured cytosolic Hb in thousands of uninfected and infected RBCs across the 48-h asexual cycle. Hb content varied widely among uninfected cells, and after invasion, infected cells mirrored and amplified this distribution: variability increased from 17% in uninfected RBCs to >100% in schizonts. A minimal predator-prey model accurately reproduced the observed spread in parasite Hb consumption, showing that host variability alone can generate much of the diversity in parasite feeding rates traditionally attributed to parasite factors. These findings provide the first evidence that host phenotypic noise drives variation in Hb consumption among genetically identical parasites. Incorporating host-to-host variability into within-host models could improve predictions of parasite growth, refine the activation kinetics of Hb-dependent antimalarials, and reveal analogous principles in other intracellular infections where host variability and host-parasite crosstalk can shape pathogen outcomes. This systems-level perspective emphasizes the need to account for host heterogeneity in both experimental design and therapeutic strategies. IMPORTANCE Cell-to-cell phenotypic variability is a fundamental feature of living systems, yet its impact on host-pathogen interactions has been largely overlooked. Here, we show that natural, non-genetic variation in red blood cell hemoglobin strongly shapes how Plasmodium falciparum —the most lethal malaria parasite—consumes Hb inside host cells. Using quantitative imaging and a mathematical model, we demonstrate that host variability alone can explain much of the observed differences in parasite feeding rates. This perspective reframes parasite Hb consumption as an emergent property of host-parasite interactions. More broadly, it highlights how natural variability among host cells can influence the course of intracellular infections, with potential implications for predicting pathogen growth and optimizing drug treatment strategies.