Plasmodium falciparum Line-Dependent Association of In Vitro Growth-Inhibitory Activity and Risk of Malaria

Abstract

e Plasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA) in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using three P. falciparum lines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96; P ‫؍‬ 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on the P. falciparum line and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence of P. falciparum erythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

Bacterially Expressed Full-Length Recombinant Plasmodium falciparum RH5 Protein Binds Erythrocytes and Elicits Potent Strain-Transcending Parasite-Neutralizing Antibodies

“…The ability to impede erythrocyte invasion by P. falciparum merozoites can be quantitated in an in vitro invasion inhibition or growth inhibition assay (GIA) that has been widely reported in the field. A significant association of invasion inhibition measured in vitro with a reduced risk of malaria has also been reported previously (37,38), and thus, in vitro invasion-inhibition appears to be a useful surrogate marker to predict the functional efficacy of antibodies induced by a blood-stage vaccine. In spite of the extensive research on the parasite biology of P. falciparum, it has been difficult to demonstrate potent invasion-inhibitory activity, with the exception of antibodies against apical membrane antigen 1 (AMA-1) (39,40).…”

Transplacentally transferred functional antibodies against Plasmodium falciparum decrease with age

“…We and others have shown that children and adults with higher levels of GIA are associated with protection from malaria infection or clinical disease (Crompton et al, 2010; Dent et al, 2006; Rono et al, 2012a). Interestingly, adults can have lower levels of GIA than children (Dent et al, 2006; McCallum et al, 2008).…”

Acquired Antibodies to Merozoite Antigens in Children from Uganda with Uncomplicated or Severe Plasmodium falciparum Malaria

“…In previous studies where this method has been applied, mainly laboratory strains have been used, and it has been reported that antibodies that inhibit merozoite invasion could contribute to acquisition of natural immunity but may not necessarily confer definitive protective immunity against malaria; there are conflicting results as to whether the inhibitory effect of antibodies increases or decreases with age (31,33,35,36,38,39,98). In our study, we used two clinical P. falciparum isolates, UAM37 and UAS31, to investigate whether there is decreased invasion in the presence of plasma from patients with uncomplicated and severe malaria.…”

“…These naturally acquired inhibitory antibodies (causing reduced invasion of parasite isolates) are present in many clinically immune individuals but more seldom in susceptible individuals, and levels are higher in areas with higher levels of malaria transmission (36). Some studies have shown a protective effect of inhibitory antibod-ies (33,38,39); however, the association between the inhibitory activity of antibodies and protection in malaria remains unclear (35,36,40).…”