Abstract
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is considered to be the main variant surface antigen (VSA) of Plasmodium falciparum and is mainly localized on electron-dense knobs in the membrane of the infected erythrocyte. Switches in PfEMP1 expression provide the basis for antigenic variation and are thought to be critical for parasite persistence during chronic infections. Recently, strain transcending anti-PfEMP1 immunity has been shown to develop early in life, challenging the role of PfEMP1 in antigenic variation during chronic infections. In this work we investigate how P. falciparum achieves persistence during a chronic asymptomatic infection. The infected individual (MOA) was parasitemic for 42 days and multilocus var gene genotyping showed persistence of the same parasite population throughout the infection. Parasites from the beginning of the infection were adapted to tissue culture and cloned by limiting dilution. Flow cytometry using convalescent serum detected a variable surface recognition signal on isogenic clonal parasites. Quantitative real-time PCR with a field isolate specific var gene primer set showed that the surface recognition signal was not correlated with transcription of individual var genes. Strain transcending anti-PfEMP1 immunity of the convalescent serum was demonstrated with CD36 selected and PfEMP1 knock-down NF54 clones. In contrast, knock-down of PfEMP1 did not have an effect on the antibody recognition signal in MOA clones. Trypsinisation of the membrane surface proteins abolished the surface recognition signal and immune electron microscopy revealed that antibodies from the convalescent serum bound to membrane areas without knobs and with knobs. Together the data indicate that PfEMP1 is not the main variable surface antigen during a chronic infection and suggest a role for trypsin sensitive non-PfEMP1 VSAs for parasite persistence in chronic infections.
Highlights
P. falciparum is responsible for the most severe form of human malaria and is a major cause for morbidity and mortality in sub-Saharan Africa [1]
Semi-immunity against P. falciparum is associated with the development of antibodies [2,3] against variant surface antigens (VSAs) expressed on infected red blood cells [4,5,6]
To test whether a part of the parasite population was able to avoid the hosts immune system, we investigated the humoral immune response against surface antigens of the MOA bulk strain and the 19 MOA clones with convalescent serum obtained on day 70 of the investigation
Summary
P. falciparum is responsible for the most severe form of human malaria and is a major cause for morbidity and mortality in sub-Saharan Africa [1]. In vitro switching investigations with long term laboratory strains and with parasites obtained from controlled human infections [28,29,30,31,32], provide evidence that var gene switching is highly structured and suggest a repeatable hierarchy of var gene activation. These observations raise the question of how such a stably inherited transcription pattern is compatible with antigenic variation during natural chronic infections in endemic areas
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