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

Neha Thakre,Priyanka Fernandes,Ann-Kristin Mueller,Frederik Graw

doi:10.3389/fmicb.2018.00166

Neha Thakre, Priyanka Fernandes + Show 2 more

Open Access

https://doi.org/10.3389/fmicb.2018.00166

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Abstract

The blood-stage of the Plasmodium 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 Plasmodium parasites have not been completely identified so far. Using the Plasmodium berghei mouse model for malaria, we characterized and compared the blood-stage infection dynamics of PbANKA WT and a mutant parasite strain lacking a novel Plasmodium antigen, PbmaLS_05, that is well conserved in both human and animal Plasmodium parasite strains. Infection of mice with parasites lacking PbmaLS_05 leads to lower parasitemia levels and less severe disease progression in contrast to mice infected with the wildtype PbANKA strain. To specifically determine the effect of deleting PbmaLS_05 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 PbANKA and PbmaLS_05 (-) parasite strains differed in their infectivity potential during the early intra-erythrocytic stage of infection. Parasites lacking PbmaLS_05 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 PbmaLS_05 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.

Highlights

Malaria caused by the Plasmodium parasite is one of the most serious tropical diseases with a major impact on global health
Parasite replication and invasion of red blood cells during the pathological blood-stage of the Plasmodium life cycle is a critical determinant of the severity of disease progression in a malaria infection (Beeson et al, 2016)
We used an agestructured model based on partial differential equations similar to previous approaches (Antia et al, 2008) to determine differences between PbANKA (WT) and PbmaLS_05 (-) (KO) parasite strains in terms of age-preferences for red blood cells (RBC), and in particular reticulocytes

Summary

Introduction

Malaria caused by the Plasmodium parasite is one of the most serious tropical diseases with a major impact on global health. Many Plasmodium parasite strains have been found to differ in their infectivity during the blood-stage infection phase by targeting RBC of different ages (McQueen and McKenzie, 2004). Strains of Plasmodium chabaudi show such age-specific targeting of RBC during the acute infection phase (Antia et al, 2008), while Plasmodium berghei (Singer et al, 1955; McNally et al, 1992; Sexton et al, 2004; Cromer et al, 2006, 2009) has an estimated ∼150-fold preference for reticulocytes during the late stages of infection (Cromer et al, 2006). Which factors govern and influence the infectivity of parasites and to which extent elevated parasite densities might influence faster disease progression have not been determined so far (Beeson et al, 2016)

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