Erythrocyte polymorphisms and malaria parasite invasion in Papua New Guinea

Abstract

Plasmodium falciparum merozoites engage the erythrocyte surface through several receptor (host)-ligand (parasite) interactions during a brief exchange that results in parasite invasion of the red blood cell. Tens of thousands of these events occur during the initial cycle of blood-stage infections but advance towards billions as the parasite becomes visible to microscopists attempting to diagnose the underlying cause of illness in febrile patients. Advancing blood-stage infection leads to massive proportions of erythrocytes that rupture during repetitive cycles of asexual reproduction. As the infection leads to illness, non-immune or semi-immune individuals can suffer from life-threatening consequences of severe malarial anemia that play a leading role in pathogenesis. Through natural selection, some erythrocyte membrane polymorphisms are likely to have reduced the invasion success of the P. falciparum merozoite and increased the fitness of the human host population.In the mid-1970s, initial insights into the molecular nature of the interactions between erythrocyte surface proteins and malaria parasites were gained using Plasmodium knowlesi, a simian parasite amenable to in vitro culture [1]. These studies ultimately led to the discovery that the erythrocyte membrane protein carrying the Duffy blood group was a crucial invasion receptor for Plasmodium knowlesi and the related human parasite Plasmodium vivax [2,3]. These seminal experiments performed by Louis Miller and his colleagues paved the way to the exploration of two key concepts that underlie susceptibility of the red blood cell to malaria infection [4]. First, specific proteins on the erythrocyte surface are co-opted by the merozoite to activate and promote parasite invasion [5,6]. This hypothesis implies that parasite proteins somehow bind erythrocyte receptors and work in partnership as the merozoite pulls itself into the cell and forms the parasitophorous vacuole. Second, polymorphisms that modify the structure or level of expression of erythrocyte membrane proteins alter the efficiency of invasion and, ultimately, susceptibility to malaria. As malaria kills millions of children each year in endemic areas, mutations that diminish the efficiency of the invasion process would confer a selective advantage to the host and might be expected to increase in frequency over time through natural selection. Given the relatively short generation time of malaria compared with humans (asexual stages of 2-4

Population Genetics of GYPB and Association Study between GYPB*S/s Polymorphism and Susceptibility to P. falciparum Infection in the Brazilian Amazon

“…In this study we took into consideration the possible confounding factor of ethnicity by performing association analyses adjusted for admixture, as well as for age and gender (Table 1). An association between other human receptor polymorphisms and variations in the parasite ligands of P. falciparum that modulate susceptibility to malaria, was also demonstrated [25], [74]–[76].…”

A Novel ENU-Mutation in Ankyrin-1 Disrupts Malaria Parasite Maturation in Red Blood Cells of Mice

“…Several such red cell disorders are also associated with resistance to malarial infection [14]–[18]. For example, individuals with hereditary elliptocytosis have deficiencies in either protein 4.1 or glycophorin C and have been reported to show resistance towards malaria infections [19].…”

In Vivo Transcriptome ofPlasmodium falciparumReveals Overexpression of Transcripts That Encode Surface Proteins

“…Patients infected with P. falciparum present with a range of outcomes, from asymptomatic parasitemia to severe disease and death. The host and parasite factors that mediate the severity of disease are only partially defined [3][4][5][6][7][8][9]. One approach to the identification of parasite virulence factors is the characterization of in vivo parasite biological pro- adults who presented with fever and whose blood smears were positive for P. falciparum were enrolled in the study.…”