PfEMP1 and var genes - Still of key importance in Plasmodium falciparum malaria pathogenesis and immunity

Abstract

The most severe form of malaria, caused by infection with Plasmodium falciparum parasites, continues to be an important cause of human suffering and poverty. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of clonally variant antigens, which mediates the adhesion of infected erythrocytes to the vascular endothelium in various tissues and organs, is a central component of the pathogenesis of the disease and a key target of the acquired immune response to malaria. Much new knowledge has accumulated since we published a systematic overview of the PfEMP1 family almost ten years ago. In this chapter, we therefore aim to summarize research progress since 2015 on the structure, function, regulation etc. of this key protein family of arguably the most important human parasite. Recent insights regarding PfEMP1-specific immune responses and PfEMP1-specific vaccination against malaria, as well as an outlook for the coming years are also covered.

Keywords: Immunity; Malaria; Pathogenesis; PfEMP1; Plasmodium falciparum; Structure/function; Vaccine; var genes.

Figure 1.. General organization of var genes and associated regulatory elements.

Transcription of the PfEMP1 encoding mRNA initiates at upstream promoter regions of four basic types, referred to as Ups A/B/C or E [A]. Ups E promoter types are associated with an upstream open reading frame (uORF) positioned between the transcription start site and the PfEMP1 coding region. This serves as a translational repressor and a protein export motif [B]. All var genes contain a bidirectional promoter situated within a conserved intron that gives rise to both sense and antisense noncoding RNAs (ncRNAs). The antisense ncRNA has been associated specifically with the active var gene [C]. A unique class of ncRNAs called RUF6 transcribed by RNA polymerase III are found at 15 loci within the parasite’s genome at positions within or adjacent to clusters of var genes. Transcription of these ncRNAs has been associated with var transcriptional activation [D]. Variable chromatin structure is associated with activation and silencing of var gene transcription. These histone modifications extend across the entire promoter region, including the transcription start site and most of exon 1 [E].

Figure 2.. PfEMP1-specific IgG induced by natural infection and by subunit vaccination.

Exposure to native, conformationally intact PfEMP1 [A] induces afucosylated IgG that induces ADCC [B], that can recognize complex and inter-clonally conserved epitopes [C], and that inhibits IE adhesion [D]. Subunit vaccination with soluble, recombinant oligo-domain, conformationally compromised PfEMP1 [E] induces fucosylated IgG that cannot induce ADCC [F], recognizes epitopes that are often simple and allelic variant-specific [G], and with limited capacity to neutralize IE adhesion [H].