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Randomized Controlled Trial
. 2017 Aug 23;17(1):585.
doi: 10.1186/s12879-017-2686-0.

Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure

Abdirahman I Abdi  1   2 , Susanne H Hodgson  3 , Michelle K Muthui  4 , Cheryl A Kivisi  4   5 , Gathoni Kamuyu  4 , Domtila Kimani  4 , Stephen L Hoffman  6 , Elizabeth Juma  7   8 , Bernhards Ogutu  7   8 , Simon J Draper  3 , Faith Osier  4 , Philip Bejon  4 , Kevin Marsh  4 , Peter C Bull  9
Affiliations
Randomized Controlled Trial

Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure

Abdirahman I Abdi et al. BMC Infect Dis. .

Abstract

Background: The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells. Previous studies have suggested that parasites expressing PfEMP1 subclasses group A and DC8, associated with severe malaria, may have a growth advantage in immunologically naïve individuals. However, this idea has not been tested in longitudinal studies.

Methods: Here we assessed expression of the var genes encoding PfEMP1, in parasites sampled from volunteers with varying prior exposure to malaria, following experimental infection by sporozoites (PfSPZ). Using qPCR, we tested for associations between the expression of various var subgroups in surviving parasite populations from each volunteer and 1) the levels of participants' antibodies to infected erythrocytes before challenge infection and 2) the apparent in vivo parasite multiplication rate.

Results: We show that 1) expression of var genes encoding for group A and DC8-like PfEMP1 were associated with low levels of antibodies to infected erythrocytes (αIE) before challenge, and 2) expression of a DC8-like CIDRα1.1 domain was associated with higher apparent parasite multiplication rate in a manner that was independent of levels of prior antibodies to infected erythrocytes.

Conclusions: This study provides insight into the role of antibodies to infected erythrocytes surface antigens in the development of naturally acquired immunity and may help explain why specific PfEMP1 variants may be associated with severe malaria.

Trial registration: Pan African Clinical Trial Registry: PACTR201211000433272 . Date of registration: 10th October 2012.

Keywords: Antibodies; Controlled human malaria infection (CHMI); Immunity; P. falciparum; PfEMP1; Sporozoite.

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Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained from Kenya Medical Research Institute Scientific and Ethical Review Unit (KEMRI-SERU) and written informed consent was obtained from the study participants who were all Kenyan adults. The study methods were carried out in accordance with the approved guidelines.

Consent for publication

This paper was published with the permission of the director of KEMRI.

Competing interests

Sanaria Inc. manufactured PfSPZ challenge used in the study. Thus, Stephen L. Hoffman has potential conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Naturally acquired pre-challenge IE surface antibodies (αIE). a Dot plot showing the αIE levels in relation to prior exposure to P. falciparum (Mann-Whitney U test). The red bar indicates the median level. b-d shows IE surface staining of IgG from participant 110 (b), a hyperimmune Kilifi adult (c), pooled naïve European sera (d). The upper right quadrant shows the percentage of IE recognized by the antibodies. e-f αIE association with anti-MSP-2 (e) and anti-schizont extract (f). g Relationship between PMR and αIE, p value was calculated using Spearman’s correlation coefficient. MinExp = minimal prior exposure, DefExp = Definite prior exposure, Neg ctrl = negative control, post ctrl = positive control. αIE = antibodies to IE, OD = optical density, MSP-2 = merozoite surface protein 2, AB = sera from AB blood group, mdfi = median fluorescent intensity. αIE level for participant 110 is highlighted in blue
Fig. 2
Fig. 2
Proposed model to explain the inter-relationships between antibodies, var expression and apparent parasite multiplication rate (PMR). a In the absence of αIE antibodies, parasites expressing a subset of “dominant” PfEMP1 with high intrinsic cytoadhesive capacity dominate the infection (black) because of their ability to limit splenic parasite clearance rate. b As a result, these variants will be the first to be recognized by the developing host antibody response. c The surviving parasites express PfEMP1 variants that can evade antibodies, but because they have a lower intrinsic cytoadhesive capacity, these parasites have a higher splenic clearance rate, resulting in a lower observed apparent PMR. The thick grey horizontal line represents the endothelial cells that make up the inner wall of microvessels. d under a model of variant specific immunity, dominant variants (orange shapes) may arise that are poorly recognised by antibodies carried by the host population (grey rectangles) allowing them to establish infections (arrows). Their expression levels would be correlated with growth rate but poorly correlated with bulk measures of pre-infection antibodies
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