Examining the Reticulocyte Preference of Two Plasmodium berghei Strains during Blood-Stage Malaria Infection

Abstract

The blood-stage of the <i>Plasmodium</i> parasite is one of the key phases within its life cycle that influences disease progression during a malaria infection. The efficiency of the parasite in infecting red blood cells (RBC) determines parasite load and parasite-induced hemolysis that is responsible for the development of anemia and potentially drives severe disease progression. However, the molecular factors defining the infectivity of <i>Plasmodium</i> parasites have not been completely identified so far. Using the <i>Plasmodium berghei</i> mouse model for malaria, we characterized and compared the blood-stage infection dynamics of <i>Pb</i>ANKA WT and a mutant parasite strain lacking a novel <i>Plasmodium</i> antigen, <i>Pb</i>maLS_05, that is well conserved in both human and animal <i>Plasmodium</i> parasite strains. Infection of mice with parasites lacking <i>PbmaLS_05</i> leads to lower parasitemia levels and less severe disease progression in contrast to mice infected with the wildtype <i>Pb</i>ANKA strain. To specifically determine the effect of deleting <i>PbmaLS_05</i> on parasite infectivity we developed a mathematical model describing erythropoiesis and malarial infection of RBC. By applying our model to experimental data studying infection dynamics under normal and drug-induced altered erythropoietic conditions, we found that both <i>Pb</i>ANKA and <i>PbmaLS_05</i> (-) parasite strains differed in their infectivity potential during the early intra-erythrocytic stage of infection. Parasites lacking <i>PbmaLS_05</i> showed a decreased ability to infect RBC, and immature reticulocytes in particular that are usually a preferential target of the parasite. These altered infectivity characteristics limit parasite burden and affect disease progression. Our integrative analysis combining mathematical models and experimental data suggests that deletion of <i>PbmaLS_05</i> affects productive infection of reticulocytes, which makes this antigen a useful target to analyze the actual processes relating RBC preferences to the development of severe disease outcomes in malaria.