Abstract
Sequence diversity in pathogen antigens is an obstacle to the development of interventions against many infectious diseases. In malaria caused by Plasmodium falciparum, the PfEMP1 family of variant surface antigens encoded by var genes are adhesion molecules that play a pivotal role in malaria pathogenesis and clinical disease. PfEMP1 is a major target of protective immunity, however, development of drugs or vaccines based on PfEMP1 is problematic due to extensive sequence diversity within the PfEMP1 family. Here we identified the PfEMP1 variants transcribed by P. falciparum strains selected for a virulence-associated adhesion phenotype (IgM-positive rosetting). The parasites transcribed a subset of Group A PfEMP1 variants characterised by an unusual PfEMP1 architecture and a distinct N-terminal domain (either DBLα1.5 or DBLα1.8 type). Antibodies raised in rabbits against the N-terminal domains showed functional activity (surface reactivity with live infected erythrocytes (IEs), rosette inhibition and induction of phagocytosis of IEs) down to low concentrations (<10 µg/ml of total IgG) against homologous parasites. Furthermore, the antibodies showed broad cross-reactivity against heterologous parasite strains with the same rosetting phenotype, including clinical isolates from four sub-Saharan African countries that showed surface reactivity with either DBLα1.5 antibodies (variant HB3var6) or DBLα1.8 antibodies (variant TM284var1). These data show that parasites with a virulence-associated adhesion phenotype share IE surface epitopes that can be targeted by strain-transcending antibodies to PfEMP1. The existence of shared surface epitopes amongst functionally similar disease-associated P. falciparum parasite isolates suggests that development of therapeutic interventions to prevent severe malaria is a realistic goal.
Highlights
The design of new drugs and vaccines against many infectious diseases is hindered by sequence diversity in key pathogen antigens [1]
Life-threatening malaria is linked to a process called rosetting, in which malaria parasite-infected red blood cells bind to uninfected red cells to form aggregates that block blood flow in vital organs such as the brain
We raised antibodies against the rosette-mediating proteins, and found that they crossreacted with multiple rosetting parasite strains from different countries around the world, including samples collected directly from African children with severe malaria
Summary
The design of new drugs and vaccines against many infectious diseases is hindered by sequence diversity in key pathogen antigens [1]. This is a particular problem in the deadliest form of human malaria caused by P. falciparum, in which important targets of protective immunity are highly variable antigens (PfEMP1 variants, encoded by var genes) expressed on the surface of IEs [2]. Surface-reactive antibodies to PfEMP1 on live IEs that occur after natural infections [11,12] or after immunization with recombinant PfEMP1 domains [12,13] are predominantly variant- and strain-specific, as expected for highly variable parasite antigens. Antigenically-restricted subsets of parasite surface antigens that induce strain-transcending antibodies have not yet been identified
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