Noisy hemoglobin consumption by erythrocytic Plasmodium falciparum parasites: origins and possible implications

Non-genetic cell-to-cell phenotypic differences can significantly impact pathogen physiol-ogy and virulence, leading to unexpected phenomena such as antibiotic persistence. Here, we introduce the role of such non-genetic phenotypic differences in the host, with a focus on hemoglobin consumption by Plasmodium falciparum during the erythrocytic stage of parasite development. Through imaging, we quantified the substantial variability in hemoglobin (Hb) concentration among uninfected red blood cells (RBCs), and subse-quently measured the rate of Hb consumption by parasites at different stages of their life cycle. This revealed a similarly significant variability among different infected RBCs. By employing a mathematical model, we demonstrated that this variability in Hb consumption can be attributed to non-genetic differences in host RBCs, marking the first evidence of this phenomenon in malaria parasite physiology. These findings underscore the im-portance of incorporating non-genetic host variability into models of disease progression and treatment strategies for malaria and potentially other pathogen-related diseases.